Indazoles substituted with 1,1-dioxoisothiazolidine useful as inhibitors of cell proliferation

ABSTRACT

The present invention relates to an indazole derivative, pharmaceutically acceptable salt, solvated product and isomer thereof substituted with 1,1-dioxoisothiazolidine which are useful as inhibitors for Cyclin Dependent Kinase(CDK). The present invention also relates to an agent for inhibiting and treating diseases involving cell proliferation, e.g., cancer, inflammation, restenosis, angiogenesis, etc. which comprises the compound of formula (1) as an active ingredient together with a pharmaceutically acceptable carrier.

TECHNICAL FIELD

The present invention relates to a novel indazole derivative representedby the following formula (1):

in which

n represents 0, 1, 2 or 3,

X represents oxygen, sulfur or nitrogen atom,

R¹ and R² each independently represent hydrogen, amino, hydroxy, loweralkyl or cycloalkyl, or together form cycloalkyl,

R³ represents hydrogen; lower alkyl; phenyl or naphthyl which may beunsubstituted or substituted with one to three substituents selectedfrom the group consisting of hydroxy, halogen, nitro, amide, ester,carboxy, cyano, amidinyl, —O—R⁵, —NR⁶R⁷, phenyl, alkylsulfanyl, R⁸—SO₂—,lower alkyl, lower alkyl substituted with R⁹, pyridinyl, piperidinyl,morpholinyl, piperazinyl, thienyl and furyl; aromatic and bicyclicaromatic compounds bearing at least one heteroatom selected fromnitrogen, oxygen or sulfur atom; C₃₋₇-cycloalkyl bearing at least oneheteroatom selected from nitrogen, oxygen or sulfur atom; piperazinyl,imidazolyl, morpholinyl or piperidinyl which may be unsubstituted orsubstituted with one or two substituents selected from the groupconsisting of lower alkyl, phenyl, phenyl substituted with halogen,phenyl substituted with alkoxy, phenyl substituted with alkylcarbonyl,biphenyl and naphthyl; thiazole which may be unsubstituted orsubstituted with amino, mono- or di-lower alkylamino,alkylcarbonylamino, benzylamino, benzyloxycarbonylamino,benzyloxybenzylamino or alkoxycarbonylamino; benzodioxol; isoquinoline;indolyl; or benzimidazole wherein R⁵ represents phenyl, benzyl, loweralkyl, alkoxyalkyl, alkoxyalkoxylalkyl, alkoxyalkoxyalkoxyalkyl,aminoalkyl or mono- or di-alkylaminoalkyl, R⁶ and R⁷ are identifical ordifferent from each other and represent hydrogen, lower alkyl, oxygen orbenzyl, or joined to form a ring, and R⁸ and R⁹ represent eachindependently lower alkyl, amino, morpholinyl, piperazinyl,N-alkylpiperazinyl or imidazole, and

R⁴ represents nothing when X is oxygen or sulfur atom, but representshydroxy or alkoxy when X is nitrogen atom,

pharmaceutically acceptable salt, solvated product and isomer thereofwhich are useful as inhibitors for Cyclin Dependent Kinase(hereinafter,refered to as “CDK”), and method for preparing the same.

The present invention also relates to an agent for inhibiting andtreating diseases involving cell proliferation such as cancer,inflammation, restenosis and angiogenesis which comprises the compoundof formula (1) as an active ingredient together with a pharmaceuticalcarrier.

BACKGROUND ART

Researches on cell division process in molecular level have beenextensively performed from the late 1980's through study of division offrog oocytes, analysis several yeast cell growth or characterization ofinduced mutants by radiation and study of the tumor suppressor Rb. Inthe 1990's, it is discovered that small molecular cell growth regulatorcontrols cell division process(i.e. growth, differentiation,cytogenesis, aging and apoptosis etc.) through its own regulatoryfunction. These results were very useful for more precise understandingof the pathology of several diseases.

A representative example is cancer. In transformation process fromnormal cells to cancer cells, it was frequently observed that cellgrowth regulator loses its own function. That is to say, in cancercells, the cell growth regulator shows an abnormal activity, which isdeeply associated with invasion/metastasis which is crucial in thecancerpathology. Particularly, cell cycle deregulation is recognized tobe a direct cause of cancer since cancer occurs in experimental animalwhen overexpression or knock-out of cell growth regulator is induced byusing tranformed animal.

The cell growth is under positive or negative regulation in the samemanner as other biological regulations. The major pathway of cell cycleregulation known up to now is based on CDK activity and, as a result ofstudies on many cancer cells and carcinogenesis mechanisms, it wasconfirmed that problems of positive or negative regulation on CDKactivity result in carcinogenesis in many cases. That is, cancer mayoccur when positive or negative regulation and timely regulation whichis important for cell growth regulation are disrupted.

The representative CDKs of mammals are CDK4(Cyclin dependent kinase 4)and CDK2 which show their activity in G1-S phase of cell cycle,CDC2(CDK1) which shows its activity in G2-M phase, and so on. It isknown that CDK4 and CDK2 activities are regulated by check point of G1-Scell cycle and CDC2 activity by check point of G2-M. In many cancercells, abnormalities appear in the regulatory mechanism of CDK4, CDK2and CDC2(CDK1) and in fact, it was confirmed that induced abnormalitiescause cancer in the transformed animal. Therefore, CDK4, CDK2 andCDC2(CDK1) among several kinds of CDKs are suitable as a target ofanti-cancer agents.

The results of studies on relation between these CDKs and carcinogenesiswill be explained in more detail in the following,

The relation between the abnormal regulation of CDK4 activity andcarcinogenesis is observed in several cancer tissues. The deletion ofp16 and p15 genes generating proteins which inhibit CDK4 activity andthe overexpression of cyclin D1 indispensable for CDK4 activity areobserved in several kinds of cancer, which suggests that malignantphenotype may be expressed when CDK4 activity is deregulated.Furthermore, it was reported that p16 knocked-out mouse has such a highcarcinogenesis rate as p53 knocked-out mouse, which suggests thatmalfunction of p16 on CDK4 regulation is a cause of carcinogenesis. Fromthese experimental results, deregulation of CDK4 activity may be a causeof carcinogenesis and play a role in maintenance of phenotype of cancercell. Therefore, CDK4 inhibitors may have anti-cancer effects.

It was reported that overexpression of cyclin E indispensible for CDK2activity is observed in some breast cancers, deeply associated withmetastasis of breast cancer, inhibits cell apoptosis under low serumcondition and induces anchorage independent growth, and thathyperproliferation and neoplasia of mammary epithelial cells areobserved in transformed animal with overexpressed CDK2 by MMTV promoter,which suggests that CDK2 activity is related with the progress ormaintenance of cell transformation and CDK2 inhibitors may also haveanti-cancer effects.

Furthermore, it is discovered that CDC2(CDK1), CDK3, CDK5, CDK6 and CDK7play an important role in each phase of cell division. These areclassified into CDKs family. In addition to cyclin D1 and E, cyclin A,B, C, D2, D3, D4, F and G are also calssified into the same family.

On the basis of the above-mentioned research, efficient inhibitors ofthese CDKs may be useful as anti-cancer agents. Therefore, recently,these inhibitors have been developed.

As effective CDK inhibitors developed hitherto, there existsFlavopiridol, compound of the formula (A):

[Ref.: EP 0,241,003(1987) and 0,336,061(1990)].

In addition, a purine derivative of the formula (B):

has been recently developed[Ref: WO 97/20842].

Recently, a CDKs inhibitor having aminopyridine structure of the formula(C):

is disclosed in WO 98/33798.

However, the CDK inhibitors developed up to now could not havesatisfactory effects.

So, the present inventors have made widespread and concentrativeresearches on CDK inhibitors, particularly indazole-based compounds, andas a result, found that a component of the formula (1) which has a quitedifferent structure from any other known CDK inhibitors inhibits CDKsenzymes effectively and finally, completed the present invention.

DISCLOSURE OF THE INVENTION

The object of the present invention is to provide a novel indazolederivative of formula (1), a process for preparing the same, and acomposition for inhibiting and treating diseases involving cellproliferation such as cancer, inflammation, restenosis and angiogenesiswhich comprises as an active ingredient the compound of formula (1). Inthis specification, CDKs include all of CDK2, CDK4, CDC2(CDK1), CDK3,CDK5, CDK6, CDK7 etc., and cyclin includes cyclin D1, E, A, B, C, D2,D3, D4, F and G

DETAILED DESCRIPTION OF THE INVENTION

Hereinafter, the present invention is explained in detail.

The present invention relates to a novel indazole derivative representedby the following formula (1):

in which

n represents 0, 1, 2 or 3,

X represents oxygen, sulfur or nitrogen atom,

R¹ and R² each independently represent hydrogen, amino, hydroxy, loweralkyl or cycloalkyl, or together form cycloalkyl,

R³ represents hydrogen; lower alkyl; phenyl or naphthyl which may beunsubstituted or substituted with one to three substituents selectedfrom the group consisting of hydroxy, halogen, nitro, amide, ester,carboxy, cyano, amidinyl, —O—R⁵, —N R⁶ R⁷, phenyl, alkylsulfanyl,R⁸—SO₂—, lower alkyl, lower alkyl substituted with R⁹, pyridinyl,piperidinyl, morpholinyl, piperazinyl, thienyl and furyl; aromatic andbicyclic aromatic compounds bearing at least one heteroatom selectedfrom nitrogen, oxygen or sulfur atom; C₃₋₇-cycloalkyl bearing at leastone heteroatom selected from nitrogen, oxygen or sulfur atom;piperazinyl, imidazolyl, morpholinyl or piperadinyl which may beunsubstituted or substituted with one or two substituents selected fromthe group consisting of lower alkyl, phenyl, phenyl substituted withhalogen, phenyl substituted with alkoxy, phenyl substituted withalkylcarbonyl, biphenyl and naphthyl; thiazole which may beunsubstituted or substituted with amino, mono- or di-lower alkylamino,alkylcarbonylamino, benzylamino, benzyloxycarbonylamino,benzyloxybenzylamino or alkoxycarbonylamino; benzodioxol; isoquinoline;indolyl; or benzimidazole wherein R⁵ represents phenyl, benzyl, loweralkyl, alkoxyalkyl, alkoxyalkoxylalkyl, alkoxyalkoxyalkoxyalkyl,aminoalkyl or mono- or di-alkylaminoalkyl, R⁶ and R⁷ are identifical ordifferent from each other and represent hydrogen, lower alkyl, oxygen orbenzyl, or joined to form a ring, and R⁸ and R⁹ represent eachindependently lower alkyl, amino, morpholinyl, piperazinyl,N-alkylpiperazinyl or imidazole, and

R⁴ represents nothing when X is oxygen or sulfur atom, but representshydroxy or alkoxy when X is nitrogen atom,

pharmaceutically acceptable salt, solvated product and isomer thereofwhich have efficacies on inhibiting and treating diseases involving cellproliferation such as cancer, inflammation, restenosis and angiogenesisthrough a mechanism of inhibiting CDKs activity.

Among the indazole derivatives of formula (1) according to the presentinvention, the preferred compounds include those wherein

n represents 1 or 2,

X represents oxygen, sulfur or nitrogen atom,

R¹ and R² each independently represent hydrogen, amino, hydroxy, loweralkyl or cycloalkyl, or together form cycloalkyl,

R³ represents hydrogen; lower alkyl; phenyl which may be unsubstitutedor substituted with one to three substituents selected from the groupconsisting of hydroxy, halogen, nitro, amide, cyano, amidinyl, —O—R⁵, —NR⁶ R⁷, phenyl, lower alkylsulfanyl, R⁸—SO₂—, lower alkyl, lower alkylsubstituted with R⁹, pyridiny, piperidinyl, morpholinyl, thienyl andfuryl; naphthyl; piperazinyl or imidazolyl which may be unsubstituted orsubstituted with one or two substituents selected from the groupconsisting of lower alkyl, phenyl, phenyl substituted with halogen,phenyl substituted with lower alkoxy, phenyl substituted with acetyl,biphenyl and naphthyl; morpholinyl; piperidinyl; thiazole which may beunsubstituted or substituted with amino, mono- or di-lower alkylamino,acetylamino, benzylamino, benzyloxyamino, benzyloxybenzylamino or loweralkoxycarbonylamino; benzodioxol; 3,4-dihydroisoquinoline; orbenzimidazole wherein R⁵ represents phenyl, benzyl, lower alkyl, loweralkoxyalkyl, polyethyleneglycolyl, aminoalkyl or mono- or di-loweralkylaminoalkyl, R⁶ and R⁷ are identifical or different from each otherand represent hydrogen, lower alkyl, oxygen or benzyl, or joined to forma ring, and R8 and R⁹ each independently represent lower alkyl, amino,morpholinyl, piperazinyl, N-alkylpiperazinyl or imidazole, and

R⁴ represents nothing when X is oxygen or sulfur atom, but representshydroxy or alkoxy when X is nitrogen atom.

The term “lower alkyl” in the substituents of the compound of formula(1) refers to a linear or branched saturated radical of from 1 to 6 Catoms such as methyl, ethyl, isopropyl, isobutyl and t-butyl. The term“lower alkoxy” refers to a linear or branched radical of from 1 to 6 Catoms such as methoxy, ethoxy, isopropoxy, isobutoxy and t-butoxy.

Since the compounds of formula (1) according to the present inventionmay have asymmetric carbon centers, they can be present in the form ofenantiomer or diastereomer, and mixtures thereof including racemate.

Therefore, the present invention also includes all these isomers andtheir mixtures.

The compound of formula (1) according to the present invention may alsoform a pharmaceutically acceptable salt. Such a salt includes non-toxicacid addition salt containing pharmaceutical acceptable anion, forexample a salt with inorganic acids such as hydrochloric acid, sulfuricacid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid,etc., a salt with organic carboxylic acids such as tartaric acid, formicacid, citric acid, acetic acid, trichloroacetic acid, trifluoroaceticacid, capric acid, isobutanoic acid, oxalic acid, malonic acid, succinicacid, phthalic acid, gluconic acid, benzoic acid, lactic acid, fumaricacid, maleic acid, etc., or a salt with sulfonic acids such asmethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,naphthalenesulfonic acid, etc.

The representative examples of the compound of formula (1) according tothe present invention are

1.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-phenylacetamide,

2.2-(3-chlorophenyl)-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide,

3.2-[4-(benzyloxy)phenyl]-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide,

4.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-(4-hydroxyphenyl)acetamide,

5.2-[4-(dibenzylamino)phenyl]-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide,

6.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-[4-(methylamino)phenyl]acetamide,

7.2-(4-aminophenyl)-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide,

8.2-(4-chlorophenyl)-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide,

9.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-(4-fluorophenyl)acetamide,

10.2-[1,1′-biphenyl]-4-yl-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide,

11.2-(3-bromophenyl)-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide,

12.2-(4-bromophenyl)-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide,

13.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-phenylethanethioamide,

14.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-N′-hydroxy-2-phenylethaneimidoamide,

15.2-(1,3-benzodioxol-5-yl)-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazole-3-yl]acetamide,

16.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-(1-naphthyl)acetamide,

17.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-(2-naphthyl)acetamide,

18.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-(3-nitrophenyl)acetamide,

19. N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide,

20.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-[4-(methylsulfanil)phenyl]acetamide,

21.2-(3-aminophenyl)-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide,

22.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]ethanethioamide,

23.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-N′-hydroxyethaneimidoamide,

24.2-(3,4-dichlorophenyl)-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide,

25.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-3-phenylpropanamide,

26.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-(4-isopropylphenyl)acetamide,

27.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-(3-methylphenyl)acetamide,

28.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-(4-methylphenyl)acetamide,

29.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-[4-(methylsulfonyl)phenyl]acetamide,

30.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-(4-methyl-1-piperazinyl)acetamide,

31.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-(4-morpholinyl)acetamide,

32.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-(1-piperidinyl)acetamide,

33.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-[4-(4-pyridinyl)phenyl]acetamide,

34.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-[4-(1-piperidinyl)phenyl]acetamide,

35.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-[4-(1-morpholinyl)phenyl]acetamide,

36.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-[4-(3-thienyl)phenyl]acetamide,

37.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-[4-(4-morpholinylsulfonyl)phenyl]acetamide,

38.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-(4-methoxyphenyl)acetamide,

39.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-[4-(2-furyl)phenyl]acetamide,

40.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-4-[(4-methyl-1-piperazinyl)sulfonyl]phenylacetamide,

41.2-(1H-benzimidazol-1-yl)-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide,

42.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-(4-ethoxyphenyl)acetamide,

43.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-[4-(4-morpholinylmethyl)phenyl]acetamide,

44.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-4-[(4-methyl-1-piperazinyl)methyl]phenylacetamide,

45.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-(4-nitrophenyl)acetamide,

46.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-[4-(1H-imidazole-1-ylmethyl)phenyl]acetamide,

47.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-(4-phenyl-1H-imidazol-1-yl)acetamide,

48.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-(4-phenyl-1-piperazinyl)acetamide,

49.2-[3,4-dihydro-2(1H)-isoquinolinyl]-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide,

50.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-[4-(4-chlorophenyl)-1-piperazinyl]acetamide,

51.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-[4-(4-methoxyphenyl)-1-piperazinyl]acetamide,

52.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-[4-(2-ethoxyphenyl)-1-piperazinyl]acetamide,

53.2-[4-(4-acetylphenyl)-1-piperazinyl]-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide,

54.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-(4-phenoxyphenyl)acetamide,

55.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-1-phenylcyclopentanecarboxamide,

56.2-cyclopentyl-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-phenylacetamide,

57.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-phenylbutanamide,

58. t-butyl4-(2-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]amino-2-oxoethyl)-1,3-thiazol-2-ylcarbamate,

59.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-4-[2-(2-ethoxyethoxy)ethoxy]phenylacetamide,

60.2-(2-amino-1,3-thiazol-4-yl)-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide,

61.2-[4-(4-bromophenyl)-1H-imidazol-1-yl]-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide,

62.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-[4-(2-naphthyl)-1H-imidazol-1-yl]acetamide,

63.2-(4-[1,1′-biphenyl]-4-yl-1H-imidazol-1-yl)-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide,

64.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-[2-(ethylamino)-1,3-thiazol-4-yl]acetamide,

65.2-[2-(diethylamino)-1,3-thiazol-4-yl]-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide,

66.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-(4-2-[2-(2-methoxyethoxy)ethoxy]ethoxyphenyl)acetamide,

67.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-(4-ethoxy-3-nitrophenyl)acetamide,

68.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-(2-methylphenyl)acetamide,

69.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-[3-(ethylamino)phenyl]acetamide,

70.2-[3-(diethylamino)phenyl]-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide,

71.2-(3,5-dimethoxyphenyl)-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide,

72.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-[4-(ethylamino)phenyl]acetamide,

73.2-[4-(diethylamino)phenyl]-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide,

74.2-(3-chloro-4-ethoxyphenyl)-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide,

75.2-[4-(2-aminoethoxy)phenyl]-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide,

76.2-[2-(acetylamino)-1,3-thiazol-4-yl]-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl-1H-indazol-3-yl]acetamide,

77.2-(2-[4-(benzyloxy)benzyl]amino-1,3-thiazol-4-yl)-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide,

78.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-(3-ethoxyphenyl)acetamide,

79.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-[4-ethoxy-3-(4-morpholinylsulfonyl)phenyl]acetamide,

80.2-[3-(aminosulfonyl)-4-ethoxyphenyl]-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide,

81.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-4-ethoxy-3-[(4-methyl-1-piperazinyl)sulfonyl]phenylacetamide,and

82.2-[4-(2-aminoethoxy)phenyl]-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide.

The processes for preparing the compound of formula (1) as defined aboveare depicted in the following Scheme (1):

wherein R¹, R², R³ and n are as previously described, and Boc representst-butoxycarbonyl.

That is, as depicted in the above Scheme (1), an amidoxime of thefollowing formula (2):

is prepared by reacting anthranilonitrile with hydroxylamine, and theamidoxime thus prepared is then reacted with ester to produce a3-aminoindazole of the following formula (3):

wherein R¹, R² and R³ are as previously described.

A 1-position of 3-aminoindazole is protected by t-butylcarbamate toproduce a compound of the following formula (4):

wherein R¹, R², R³ and n are as previously described, and Boc representst-butoxycarbonyl, and then nitro group at 5-C is reduced to produce anamine of the following formula (5):

wherein R¹, R², R³ and n are as previously described, and Boc representst-butoxycarbonyl.

A sulfonamide of the following formula (6):

wherein R¹, R², R³ and n are as previously described, and Boc representst-butoxycarbonyl, which is obtained by reacting the compound of formula(5) with sulfonyl chloride is cyclized through intramolecularring-closure to synthesize a dioxoisothiazolidine of the followingformula (7):

wherein R¹, R², R³ and n are as previously described, and Boc representst-butoxycarbonyl.

Finally, the compound of formula (7) is deprotected to give the compoundof formula (1). A compound of formula (1) wherein X is oxygen atom isreacted with Lawesson's reagent(2,4-bis-(4-methoxyphenyl-1,3-dithia-2,4-diphosphethane-2,4-disulfide)to produce a compound of formula (1) wherein X is sulfur atom, or thecompound of formula (1) wherein X is sulfur atom is reacted with acompound of the following formula (8):

R⁴—NH₂  (8)

wherein R⁴ is as previously described, to produce a compound of formula(1) wherein X is nitrogen atom:

The indazole derivative of formula (1) according to the presentinvention may also be synthesized through amidization followed bydeprotection of an indazole intermediate of the following formula (9):

wherein Cbz represents benzyloxycarbonyl.

Specifically, the indazole intermediate of formula (9) is reacted withan acyl halide of the following formula (10):

wherein R¹, R², R³ and n are as previously described in the formula (1),and X′ represents halogen, for example, Cl, or Br., and then subjectedto deprotection to give the compound of formula (1), which will bedescribed in the following Example 2.

Meanwhile, the indazole derivative of formula (9) is prepared by usinganthranilonitrile as a starting material, as depicted in the followingScheme (2):

wherein R¹, R², R³ and n are as previously described, Boc representst-butoxycarbonyl, and Cbz represents benzyloxycarbonyl.

Specifically, as depicted in the Scheme (2) above, the indazolederivative of formula (9) is prepared by reacting amidoxime ofanthralilonitrile with ethyl phenylacetate in accordance with the aboveScheme (1) to produce an indazole derivative of the following formula(11):

which corresponds to the compound of formula (1), protecting a nitrogenat 1-position of the indazole derivative by benzylcarbamate to produce acompound of the following formula (12):

wherein Cbz represents benzyloxycarbonyl, cleaving an amide bond in thecompound of formula (12) using di-t-butylcarbonate to produce a compoundof the following formula (13):

wherein Boc represents t-butoxycarbonyl, and Cbz representsbenzyloxycarbonyl, and removing t-butoxycarbonyl groups.

However, the process for preparing the compounds according to thepresent invention has been described in detail for the purpose ofillustration, but should not be interpreted to limit the invention. Thecompounds of the present invention can easily be prepared byconventional methods of organic synthesis described in the prior art orcombinations thereof, and such combinations are well known to thoseskilled in the art.

The compound of the formula (1) according to the present invention hasan inhibitory activity against CDK, and thus may be put to a good use asan agent for inhibiting and treating diseases involving cellproliferation such as cancer, inflammation, restenosis and angiogenesis.Accordingly, another object of the present invention is to provide acomposition for inhibiting and treating diseases involving cellproliferation such as cancer, inflammation, restenosis and angiogenesiswhich comprises the compound of formula (1), pharmaceutically acceptablesalt, solvated product or isomer thereof as an active ingredienttogether with a pharmaceutically acceptable carrier.

When the compound of the present invention is administered for clinicalpurpose, it is preferably administered in an amount ranging from 1.0 to50 mg/kg of body weight a day. The total daily dosage may beadministered in one time or over several times. However, the specificdosage for a specific patient can be varied according to the specificcompound used, body weight of the subject patient, sex, hygieniccondition, diet, time or method of administration, excretion rate,mixing ratio of the medicine, severity of the disease to be treated,etc.

The compound of the present invention may be administered in the form ofinjections or oral preparations.

Injections such as sterilized aqueous or oily suspension for injectionmay be prepared by using suitable dispersing agent, sufactant orsuspension agent according to the known method. As solvents to be usedfor preparing injections, water, Ringer's fluid and isotonic NaClsolution can be mentioned, and sterilized fixing oil is also used as thesolvent or suspension medium. Any non-stimulative fixing oil includingmono- or di-glyceride can be used for this purpose, and also fatty acidsuch as oleic acid can be used for injection formulation.

As the solid preparation for oral administration, capsules, tablets,pills, powders and granules, preferably capsules and tablets can bementioned. It is desirable for tablets and pills to be formulated intoenteric-coated preparation. Solid preparations may be prepared by mixingthe active compound of formula (1) according to the present inventionwith at least one carrier selected from the group consisting of inertdiluents(e.g. sucrose, lactose, starch, etc.), lubricants(e.g. magnesiumstearate), disintegrants, and binders.

When it is intended to produce the desired anti-cancer effects byadministering clinically the compound of the invention, the activecompound of the formula (1) can be administered together with at leastone agent selected from the known anti-cancer agents. In this manner, asanti-cancer agents to be administered with the compound of theinvention, 5-fluorouracil, cisplatin, doxorubicin, taxol, gemcitabine,etc. can be mentioned.

However, the preparations containing the compound according to theinvention intended for anti-cancer effect are not limited to thosedescribed above, and any preparations useful for treating and inhibitingcancers can be included.

The present invention is more specifically explained by way of thefollowing prepartions and examples. However, it should be understoodthat the present invention is not limited to these examples in anymanner.

Preparation 1 Synthesis of t-Butyl5-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-3-[(2-phenylacetyl)amino]-1H-indazol-1-carboxylate

1-1) Synthesis of 2-Amino-N-hydroxy-5-nitrobenzenecarboxyimidoamide

27.8 g (400 mmol) of hydroxylamine hydrochloride and 33.6 g (400 mmol)of sodium bicarbonate were dissolved in 140 ml of water, and then asolution of 33.6 g (200 mmol) of anthranilonitrile in 520 ml of ethanolwas added thereto. The mixture was heated under reflux for 12 hours, andthen cooled to room temperature. The resulting precipitate was filteredand washed with water and diethyl ether to give 37.2 g of the titlecompound in a yield of 95%.

¹H NMR (DMSO-d₆, ppm): δ 6.02 (2H, s), 7.78 (1H, d), 7.80 (2H, s), 7.92(1H, dd), 8.35 (1H, d), 9.98 (1H, s); FAB MS(m/e)=197[M+1].

1-2) Synthesis of N-(5-Nitro-1H-indazol-3-yl)-2-phenylacetamide

29.4 g (150 mmol) of the compound obtained in Preparation 1-1) wasdissolved in 500 ml of tetrahydrofuran, and 9.0 g (60%, 225 mmol) ofsodium hydride was added thereto. The mixture was stirred at roomtemperature for 30 minutes. 36.9 g (225 mmol) of ethyl phenylacetate wasadded thereto, the mixture was stirred for one hour, and then 200 ml ofN,N-dimethylformamide was added thereto. The mixture was further stirredunder slight heating for 4 hours. The solvent was removed under reducedpressure, and the residue was then treated with ethyl acetate and water.The resulting precipitate was filtered and washed with water and diethyllether to give 20.3 g of the title compound in a yield of 48%.

¹H NMR (DMSO-d₆, ppm): δ 3.79 (2H, s), 7.28 (1H, t), 7.30-7.43 (4H, m),7.60 (1H, d), 8.12 (1H, dd), 9.00 (1H, s); FAB MS(m/e)=283 [M+1].

1-3) Synthesis of t-Butyl5-Nitro-3-[(2-phenylacetyl)amino]-1H-indazol-1-carboxylate

8.0 g (28 mmol) of the compound obtained in Preparation 1-2) wasdissolved in 130 Ml of tetrahydrofuran, and 3.2 g (80 mmol) of sodiumhydroxide in 20 ml of water and 7.1 g (33 mmol) of di-t-butylcarbonatewere added thereto. The mixture was stirred for one hour. After removalof solvents under reduced pressure, the residue was subjected torecrystalization using ethyl acetate and hexane to give the titlecompound quantatively.

¹H NMR(CDCl₃, ppm): δ 1.69 (9H, s), 3.65 (2H, s), 7.24-7.30 (5H, m),7.68 (1H, dd), 7.91 (1H, s), 8.00 (1H, d), 8.73 (1H, s).

1-4) Synthesis of t-Butyl5-Amino-3-[(2-phenylacetyl)amino]-1H-indazol-1-carboxylate

11 g (28 mmol) of the compound obtained in Preparation 1-3) wasdissolved in methanol, and palladium-adsorbed activated carbon (10%) wasadded thereto. The mixture was stirred under hydrogen atmosphere for 2hours. The resulting suspension was filtered through celite, and thenthe filtrate was concentrated to give the title compound quantatively.

¹H NMR (CDCl₃, ppm): δ 1.68 (9H, s), 3.68 (2H, s), 7.25-7.31 (5H, m),7.45 (1H, dd), 7.71 (1H, s), 7.94 (1H, d), 8.64 (1H, s).

1-5) Synthesis of t-Butyl5-[[(3-Chloropropyl)sulfonyl]amino]-3-[(2-phenylacetyl)amino]-1H-indazol-1-carboxylate

6.3 g (17 mmol) of the compound obtained in Preparation 1-4) wasdissolved in 120 Ml of dichloromethane, and 13 ml(170 mmol) of pyridineand 27 ml (22 mmol) of 3-chloropropanesulfonyl chloride were addedthereto. The mixture was stirred at room temperature for 2 hours. Thesolvent was removed under reduced pressure, and then the residue waspurified by silica gel columnchromatography(eluent:n-hexane/ethylacetate=1/1 (v/v)) to give the titlecompound quantatively.

¹H NMR (CD₃OD, ppm): δ 1.69 (9H, s), 2.20 (2H, m), 3.17 (2H, t), 3.65(4H, m), 7.29 (5H, m), 7.30 (1H, m), 7.40 (1H, d), 7.60 (1H, s); ESIMS(m/e)=507 [M+1].

1-6) Synthesis of t-Butyl5-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-3-[(2-phenylacetyl)amino]-1H-indazol-1-carboxylate

8.6 g (17 mmol) of the compound obtained in Preparation 1-5) wasdissolved in 150 Ml of N,N-dimethylformamide, and 1.43 g(34 mmol) ofsodium hydride was added thereto. The mixture was stirred for 30minutes. The solvent was removed under reduced pressure. The residue wasextracted with ethyl acetate, and then the extracted ethyl acetatesolution was washed with water three times. The solvent was underreduced pressure, and then the residue was purified by silica gel columnchromatography(eluent:n-hexane/ethylacetate=1/2(v/v)) to give 8.0 g ofthe title compound quantatively.

¹H NMR (CDCl₃, ppm): δ 1.70 (9H, s), 2.50 (2H, m), 3.28 (2H, t), 3.80(4H, m), 7.30 (5H, m), 7.68 (1H, m), 7.91 (1H, s), 8.00 (1H, d), 8.73(1H, s); ESI MS(m/e)=471 [M+1].

EXAMPLE 1 Synthesis ofN-[5-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-phenylacetamide(1)

5.2 g (11 mmol) of the compound obtained in Preparation 1-6) was addedto ethyl acetate which was saturated with hydrogen chloride, and themixture was stirred for 6 hours. The solvent was removed under reducedpressure to give the title compound quantatively.

¹H NMR (DMSO-d₆, ppm): δ 2.39 (2H, m), 3.46 (2H, t), 3.69 (2H, t), 3.74(2H, s), 7.26 (1H, t), 7.34 (3H, t), 7.39 (2H, d), 7.46 (1H, d), 7.58(1H, s), 10.69 (1H, s); ESI MS(m/e)=371 [M+1].

Preparation 2 Synthesis of Benzyl3-Amino-5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-1-carboxylate(indazoleIntermediate of Formula (9))

2-1) Synthesis of Benzyl5-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-3-[(2-phenylacetyl)amino]-1H-indazol-1-carboxylate

After 4.1 g(11 mmol) of the compound obtained in Example 1 was dissolvedin 150 Ml of dichloromethane, 10 ml(7.9 mmol) of triethylamine and 2.25ml (17 mmol) of benzyl chloroformate were added. The mixture was stirredfor 2 hours. After removal of solvent under reduced pressure, theresidue was purified by silica gel columnchromatography(eluent:n-hexane/ethylacetate=2/1(v/v)) to give 5.2 g ofthe title compound in a yield of 94%.

¹H NMR (DMSO-d₆, ppm): δ 2.34 (2H, m), 3.52 (2H, t), 3.74 (2H, t), 3.78(2H, s), 5.48 (2H, s), 7.25 (1H, m), 7.36 (4H, m), 7.44 (3H, m), 7.53(2H, d), 7.58 (1H, dd), 7.82 (1H, s), 8.12 (1H, d); ESI MS(m/e)=505[M+1].

2-2) Synthesis of Benzyl3-[bis(t-Butoxycarbonyl)amino]-5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-1-carboxylate

After 5.2 g (11 mmol) of the compound obtained in Preparation 2-1) wasdissolved in 100 Ml of dichloromethane, 1.36 g (11 mmol) ofN,N-dimethylaminopyridine, 1.55 ml (11 mmol) of triethylamine and 4.85g(22 mmol) of di-t-butylcarbonate were added. The mixture was stirredfor 30 minutes. After removal of solvent under reduced pressure, theresidue was purified by silica gel columnchromatography(eluent:n-hexane/ethylacetate=1/2(v/v)) to give 6.4 g ofthe title compound quantatively.

¹H NMR (CD₃OD, ppm): δ 1.36 (9H, s), 1.44 (9H, s), 2.51 (2H, m), 3.45(2H, t), 3.83 (2H, t), 5.53 (2H, s), 7.34 (3H, m), 7.48 (1H, d), 7.54(2H, d), 7.56 (1H, dd); 8.15 (1H, dd), ESI MS(m/e)=587 [M+1].

2-3) Synthesis of Benzyl3-Amino-5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-1-carboxylate

6.4 g (11 mmol) of the compound obtained in Preparation 2-2) was addedto ethyl acetate which was saturated with hydrogen chloride, and themixture was stirred for 3 hours. The mixture was neutralized withaqueous 1N sodium hydroxide solution, and the precipitate thus obtainedwas filtered under reduced pressure to give 2 g of the title compound ina yield of 47%.

¹H NMR (DMSO-d₆, ppm): δ 2.45 (2H, m), 3.53 (2H, t), 3.77 (2H, t), 5.38(2H, s), 6.42 (2H, s), 7.37 (1H, m), 7.42 (2H, m), 7.49 (3H, m), 7.71(1H, d), 7.98 (1H, d); ESI MS(m/e)=505 [M+1].

Example 2 Synthesis of2-(3-Chlorophenyl)-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide(2)

50 mg (0.13 mmol) of the compound obtained in Preparation 2 was added to10 ml of tetrahydrofuran, and 3.7 mg (0.2 mmol) of 3-chlorophenylacetylchloride was added. The mixture was heated under reflux for 2 hours.After the mixture was cooled to room temperature, 2 ml of aqueous 2Nsodium hydroxide solution was added. The mixture was stirred for 2hours. The resultant was extracted with ethyl acetate, and then theextracted ethyl acetate solution was washed with water three times.After removal of solvent under reduced pressure, the residue waspurified by silica gel columnchromatography(eluent:n-hexane/ethylacetate=1/4(v/v)) to give 21 mg ofthe title compound in a yield of 40%.

¹H NMR (CD₃OD, ppm): δ 2.49 (2H, m), 3.41 (2H, t), 3.77 (2H, t), 3.79(2H, s), 7.28 (1H, m), 7.34 (2H, m), 7.45 (3H, m), 7.60 (1H, s); ESIMS(m/e)=405 [M+1].

Example 3 Synthesis of2-[4-(Benzyloxy)phenyl]-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide(3)

The title compound was obtained in a yield of 42% according to the sameprocedure as Example 2, except that 4-benzyloxyphenylacetyl chloride wasused instead of 3-chlorophenylacetyl chloride.

¹H NMR (CD₃OD, ppm): δ 2.48 (2H, m), 3.87 (2H, t), 3.71 (2H, s), 3.75(2H, t), 5.05 (2H, s), 6.95 (2H, d), 7.32 (5H, m), 7.42 (4H, m), 7.59(1H, s); API MS(m/e)=477 [M+1].

Example 4 Synthesis ofN-[5-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-(4-hydroxyphenyl)acetamide(4)

The title compound was obtained in a yield of 35% according to the sameprocedure as Preparation 1-4), except that the compound obtained inExample 3 was used instead of the compound obtained in Preparation 1-3).

¹H NMR (CD₃OD, ppm): δ 2.49 (2H, m), 3.41 (2H, t), 3.68 (2H, s), 3.75(2H, t), 6.77 (2H, d), 7.24 (2H, d), 7.44 (2H, m), 7.53 (1H, s); ESIMS(m/e)=387 [M+1].

Example 5 Synthesis of2-[4-(Dibenzylamino)phenyl]-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide(5)

The title compound was obtained in a yield of 55% according to the sameprocedure as Example 2, except that 4-(N,N-dibenzylamino)phenylacetylchloride was used instead of 3-chlorophenylacetyl chloride.

¹H NMR (CD₃OD, ppm): δ 2.45 (2H, m), 3.37 (2H, t), 3.62 (2H, s), 3.72(2H, t), 4.62 (4H, s), 7.18 (4H, m), 7.23 (4H, m), 7.27 (4H, m), 7.43(2H, m), 7.56 (1H, s); ESI MS(m/e)=566 [M+1].

Example 6 Synthesis ofN-[5-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-[4-(methylamino)phenyl]acetamide(6)

The procedure was carried out according to the same procedure asPreparation 1-4), except that the compound obtained in Example 5 wasused instead of the compound obtained in Preparation 1-3). Then, theresidue was purified by silica gel columnchromatography(eluent:n-hexane/ethylacetate=1/3(v/v)) to give the titlecompound in a yield of 10%.

¹H NMR (CD₃OD, ppm): δ 2.51 (2H, m), 2.76 (3H, s), 3.41 (2H, t), 3.64(2H, s), 3.76 (2H, t), 6.63 (2H, d), 7.19 (2H, d), 7.43 (2H, m), 7.55(1H, s); ESI MS(m/e)=400 [M+1].

Example 7 Synthesis of2-(4-Aminophenyl)-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide(7)

The title compound was obtained in a yield of 20% according to the sameprocedure as Example 6.

¹H NMR (CD₃OD, ppm): δ 2.51 (2H, m), 3.43 (2H, t), 3.65 (2H, s), 3.76(2H, t), 6.72 (2H, d), 7.17 (2H, d), 7.46 (2H, br s), 7.52 (1 H, br s);ESI MS(m/e)=386 [M+1].

Example 8 Synthesis of2-(4-Chlorophenyl)-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide(8)

The title compound was obtained in a yield of 60% according to the sameprocedure as Example 2, except that 4-chlorophenylacetyl chloride wasused instead of 3-chlorophenylacetyl chloride.

¹H NMR (CD₃OD, ppm): δ 2.47(2H, m), 3.40 (2H, t), 3.73 (2H, t), 3.77(2H, s), 7.33 (2H, d), 7.38 (2H, d), 7.43 (2H, s), 7.56 (1H, s); ESIMS(m/e)=405 [M+1].

Example 9 Synthesis ofN-[5-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-(4-fluorophenyl)acetamide(9)

The title compound was obtained in a yield of 60% according to the sameprocedure as Example 2, except that 4-fluorophenylacetyl chloride wasused instead of 3-chlorophenylacetyl chloride.

¹H NMR (CD₃OD+CDCl₃, ppm): δ 2.18 (2H, m), 3.07 (2H, t), 3.45 (4H, m),6.69 (2H, m), 6.88 (1 H, m), 7.07 (3H, m), 7.31 (1H, s); API MS(m/e)=389[M+1].

Example 10 Synthesis of2-[1,1′-Biphenyl]-4-yl-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide(10)

The title compound was obtained in a yield of 40% according to the sameprocedure as Example 2, except that 1,1′-biphenylacetyl chloride wasused instead of 3-chlorophenylacetyl chloride.

¹H NMR (CD₃OD, ppm): δ 2.45 (2H, m), 3.38 (2H, t), 3.73 (2H, t), 3.82(2H, s), 7.30 (1H, t), 7.41 (4H, m), 7.48 (2H, d), 7.58 (6H, m); ESIMS(m/e)=447 [M+1].

Example 11 Synthesis of2-(3-Bromophenyl)-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide(11)

The title compound was obtained in a yield of 50% according to the sameprocedure as Example 2, except that 3-bromophenylacetyl chloride wasused instead of 3-chlorophenylacetyl chloride.

¹H NMR (CD₃OD, ppm): δ 2.47 (2H, m), 3.40 (2H, t), 3.76 (4H, m), 7.25(1H, t), 7.35 (2H, m), 7.44 (2H, m), 7.59 (2H, d); ESI MS(m/e)=450[M+1].

Example 12 Synthesis of2-(4-Bromophenyl)-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide(12)

The title compound was obtained in a yield of 46% according to the sameprocedure as Example 2, except that 4-bromophenylacetyl chloride wasused instead of 3-chlorophenylacetyl chloride.

¹H NMR (CD₃OD, ppm): δ 2.48 (2H, m), 3.41 (2H, t), 3.75 (4H, m), 7.33(2H, d), 7.44 (2H, s), 7.49 (dH, d), 7.56 (1H, s); ESI MS(m/e)=450[M+1].

Example 13 Synthesis ofN-[5-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-phenylethanethioamide(13)

100 mg (0.3 mmol) of the compound obtained in Example 1 was dissolved intetrahydrofuran, and then 72 mg (0.18 mmol) of Lawesson'sreagent(2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphethane-2,4-disulfide)was added thereto. The mixture was heated under, reflux for 2 hours. Thesolvent was removed under reduced pressure, and the residue was thentreated with ethyl acetate and hexane. The resulting precipitate waspurified by silica gel column chromatography(eluent:methanol/dichloromethane=5/95(v/v)) to give 80 mg of the titlecompound in a yield of 69%.

API MS(m/e)=387 [M+1].

Example 14 Synthesis ofN-[5-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-N′-hydroxy-2-phenylethaneimidoamide(14)

20 mg (0.052 mmol) of the compound obtained in Example 13 was dissolvedin methanol, and then 9 mg (0.1 mmol) of sodium bicarbonate and 7 mg(0.1 mmol) of hydroxylamine hydrochloride salt were added thereto. Themixture was heated under reflux for 2 hours. The solvent was removed byevaporation under reduced pressure, and the residue was then purified bysilica gel column chromatography(eluent:methanol/dichloromethane=5/95(v/v)) to give 4 mg of the titlecompound in a yield of 20%.

API MS(m/e)=386 [M+1].

Example 15 Synthesis of2-(1,3-Benzodioxol-5-yl)-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide(15)

The title compound was obtained in a yield of 36% according to the sameprocedure as Example 2, except that 1,3-benzodioxol-5-yl-acetyl chloridewas used instead of 3-chlorophenylacetyl chloride.

¹H NMR (DMSO-d₆, ppm): δ 2.41 (2H, m), 3.42 (2H, t), 3.62 (2H, s), 3.68(2H, t), 5.95 (2H, s), 6.82 (2H, s), 6.93 (1H, s), 7.34 (1H, d), 7.42(1H, d), 7.58 (1H, s); ESI MS(m/e)=415 [M+1].

Example 16 Synthesis ofN-[5-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-(1-naphthyl)acetamide(16)

The title compound was obtained in a yield of 60% according to the sameprocedure as Example 2, except that 1-naphthylacetyl chloride was usedinstead of 3-chlorophenylacetyl chloride.

¹H NMR (CD₃OD+CDCl₃, ppm): δ 2.47 (2H, m), 3.34 (2H, t), 3.69 (2H, t),4.24 (2H, s), 7.35 (1H, d), 7.40 (1H, dd), 7.47 (2H, m), 7.55 (3H, m),7.80 (1H, d), 7.85 (1H, d), 8.11 (1H, d); ESI MS(m/e)=421 [M+1].

Example 17 Synthesis ofN-[5-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-(2-naphthyl)acetamide(17)

The title compound was obtained in a yield of 57% according to the sameprocedure as Example 2, except that 2-naphthylacetyl chloride was usedinstead of 3-chlorophenylacetyl chloride.

¹H NMR (CD₃OD+CDCl₃, ppm): δ 2.43 (2H, m), 3.33 (2H, t), 3.66 (2H, t),3.92 (2H, s), 7.39 (4H, m), 7.49 (1H, d), 7.57 (1H, s), 7.79 (3H, m),7.84 (1H, s); ESI MS(m/e)=421 [M+1].

Example 18 Synthesis ofN-[5-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-(3-nitrophenyl)acetamide(18)

The title compound was obtained in a yield of 30% according to the sameprocedure as Example 2, except that 3-nitrophenylacetyl chloride wasused instead of 3-chlorophenylacetyl chloride.

¹H NMR (CD₃OD+DMSO-d₆, ppm): δ 2.42 (2H, m), 3.41 (2H, t), 3.68 (2H, t),3.91 (2H, s), 7.28 (1H, d), 7.34 (1H, d), 7.42 (1H, d), 7.62 (1H, s),7.82 (1H, d), 8.12(1H, d), 8.29 (1H, s); ESI MS(m/e)=415 [M+1].

Example 19 Synthesis ofN-[5-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide(19)

The title compound was obtained in a yield of 70% according to the sameprocedure as Example 2, except that acetyl chloride was used instead of3-chlorophenylacetyl chloride.

¹H NMR (DMSO-d₆, ppm): δ 2.44 (2H, m), 3.53 (2H, t), 3.77 (2H, t), 6.48(1H, s), 7.49 (1H, dd), 7.72 (1H, d), 8.18 (1H, d); API MS(m/e)=295[M+1].

Example 20 Synthesis ofN-[5-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-[4-(methylsulfanil)phenyl]acetamide(20)

The title compound was obtained in a yield of 58% according to the sameprocedure as Example 2, except that 4-(methylsulfanil)phenylacetylchloride was used instead of 3-chlorophenylacetyl chloride.

¹H NMR (CD₃OD+CDCl₃, ppm): δ 2.44 (3H, s), 2.51 (2H, m), 3.38 (2H, t),3.72 (2H, s), 3.76 (2H, t), 7.22 (2H, d), 7.32 (2H, d), 7.40 (2H, m),7.60 (1H, s); API MS(m/e)=417 [M+1].

Example 21 Synthesis of2-(3-Aminophenyl)-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide(21)

The procedure was carried out according to the same procedure asPreparation 1-4), except that the compound obtained in Example 18 wasused instead of the compound obtained in Preparation 1-3). Then, theresidue was purified by silica gel columnchromatography(eluent:n-hexane/ethylacetate=1/4(v/v)) to give the titlecompound in a yield of 28%.

¹H NMR (DMSO-d₆, ppm): δ 2.39 (2H, m), 3.47 (2H, t), 3.54 (2H, s), 3.68(2H, t), 5.11 (1H, s), 6.44 (1H, d), 6.52 (1H, d), 6.58 (1H, s), 6.96(1H, t), 7.34(1H, d), 7.45 (1H, d), 7.57 (1H, s), 10.53 (1H, s); ESIMS(m/e)=386 [M+1].

Example 22 Synthesis ofN-[5-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]ethanethioamide(22)

The procedure was carried out according to the same procedure as Example13, except that the compound obtained in Example 19 was used instead ofthe compound obtained in Example 1. Then, the residue was purified bysilica gel column chromatography(eluent:n-hexane/ethylacetate=1/4(v/v))to give the title compound in a yield of 34%.

ESI MS(m/e)=311 [M+1].

Example 23 Synthesis ofN-[5-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-N′-hydroxyethaneimidoamide(23)

20 mg (0.05 mmol) of the compound obtained in Example 22 was dissolvedin methanol, and then 9 mg(0.1 mmol) of sodium bicarbonate and 7 mg(0.1mmol) of hydroxylamine hydrochloride were added thereto. The mixture washeated under reflux for 2 hours. The solvent was removed under reducedpressure, and then the residue was purified by silica gel columnchromatography(eluent:methanol/dichloromethane=5/95(v/v)) to give 4 mgof the title compound in a yield of 20%.

ESI MS(m/e)=310 [M+1].

Example 24 Synthesis of2-(3,4-Dichlorophenyl)-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide(24)

The title compound was obtained in a yield of 67% according to the sameprocedure as Example 2, except that 3,4-dichlorophenylacetyl chloridewas used instead of 3-chlorophenylacetyl chloride.

¹H NMR (DMSO-d₆, ppm): δ 2.39 (2H, p), 3.46 (2H, t), 3.68 (2H, t), 3.78(2H, s), 7.36 (2H, m), 7.46 (1H, d), 7.56 (1H, m), 7.61 (1H, d), 7.65(1H, s); ESI MS(m/e)=439 [M+1].

Example 25 Synthesis ofN-[5-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-3-phenylpropanamide(25)

The title compound was obtained in a yield of 21% according to the sameprocedure as Example 2, except that 3-phenylpropanoyl chloride was usedinstead of 3-chlorophenylacetyl chloride.

¹H NMR (CD₃OD+CDCl₃, ppm): δ 2.50 (2H, m), 2.76 (2H, t), 3.04 (2H, t),3.40 (2H, t), 3.76 (2H, t), 7.16 (1H, m), 7.26 (4H, d), 7.40 (2H, m),7.53(1H, s); ESI MS(m/e)=385 [M+1].

Example 26 Synthesis ofN-[5-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-(4-isopropylphenyl)acetamide(26)

The title compound was obtained in a yield of 32% according to the sameprocedure as Example 2, except that 4-isopropylphenylacetyl chloride wasused instead of 3-chlorophenylacetyl chloride.

¹H NMR (CD₃OD+CDCl₃, ppm): δ 1.20 (6H, d), 2.44 (2H, m), 2.85 (1H, m),3.41 (2H, t), 3.72 (4H, m), 7.17 (2H, d), 7.30 (3H, m), 7.38 (1H, dd),7.64 (1H, s); ESI MS(m/e)=413 [M+1].

Example 27 Synthesis ofN-[5-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-1-yl-2-(3-methylphenyl)acetamide(27)

The title compound was obtained in a yield of 67% according to the sameprocedure as Example 2, except that 3-methylphenylacetyl chloride wasused instead of 3-chlorophenylacetyl chloride.

¹H NMR (CD₃OD+CDCl₃+DMSO-d₆, ppm): δ 2.30 (3H, s), 2.40 (2H, m), 3.45(2H, t), 3.67 (4H, m), 7.20 (3H, m), 7.36 (2H, m), 7.45 (1H, d), 7.58(1H, s); ESI MS(m/e)=4385 [M+1].

Example 28 Synthesis ofN-[5-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-(4-methylphenyl)acetamide(28)

The title compound was obtained in a yield of 69% according to the sameprocedure as Example 2, except that 4-methylphenylacetyl chloride wasused instead of 3-chlorophenylacetyl chloride.

¹H NMR (CD₃OD+CDCl₃+DMSO-d₆, ppm): δ 2.26 (3H, s), 2.40(2H, m), 3.38(2H, t), 3.67 (4H, m), 7.10 (1H, d), 7.17 (1H, m), 7.27 (2H, m), 7.33(1H, m), 7.40(1H, d), 7.57 (1H, s); ESI MS(m/e)=385 [M+1].

Example 29 Synthesis ofN-[5-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-14-(methylsulfonyl)phenyl]acetamide(29)

100 mg (0.26 mmol) of the compound obtained in Example 1 was dissolvedin tetrahydrofuran, and 100 mg (0.50 mmol) of 4-methylthiophenylacetylchloride was then added thereto. The mixture was heated under reflux for2 hours. The solvent was removed under reduced pressure, ethyl acetatewas added thereto, and then the organic phase was washed with water. Thesolvent was removed under reduced pressure, the solid thus obtained wasdissolved in dichloromethane, and then 60 mg(0.36 mmol) ofm-chloroperbenzoic acid was added thereto. The mixture was stirred atroom temperature for one hour. 10% sodium thiosulfate was added thereto,and then the mixture was further stirred for one hour. The organic phasewas separated and washed with water. Dichloromethane was removed, and 10ml of tetrahydrofuran and 3 ml of aqueous 2N sodium hydroxide solutionwere added to the solid. The mixture was stirred for 2 hours. Theresultant was extracted with ethyl acetate, and then the extracted ethylacetate solution was washed with water three times. The solvent wasremoved under reduced pressure, and then the residue was purified bysilica gel column chromatography(eluent:methanol/dichloromethane=5/95(v/v)) to give 60 mg of the titlecompound in a yield of 51%.

¹H NMR (DMSO-d₆, ppm): δ 2.39 (2H, p), 3.21 (3H, s), 3.46 (2H, t), 3.68(2H, t), 3.89 (2H, s), 7.34 (2H, dd), 7.46 (2H, d), 7.57 (2H, m), 7.65(2H, d), 7.91(2H, d); API MS(m/e)=449 [M+1].

Example 30 Synthesis ofN-[5-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-(4-methyl-1-piperazinyl)acetamide(30)

The procedure was carried out according to the same procedure as Example2, except that 2-bromoacetyl bromide was used instead of3-chlorophenylacetyl chloride. Then, N,N-dimethylformamide was addedthereto to form a solution. Anhydrous potassium carbonate and4-methylpiperazine were added to the solution. The mixture was stirredfor 2 hours. The solvent was removed by evaporation under reducedpressure, and then the residue was purified by silica gel columnchromatography (eluent:methanol/dichloromethane=5:95(v/v)) to give thetitle compound in a yield of 21%.

¹H NMR (CD₃OD, ppm): δ 2.48 (5H, m), 2.82 (8H, br s), 3.34 (2H, s), 3.42(2H, t), 3.80 (2H, t), 7.46 (2H, m), 7.72 (1H, s); API MS(m/e)=393[M+1].

Example 31 Synthesis ofN-[5-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-(4-morpholinyl)acetamide(31)

The title compound was obtained in a yield of 31% according to the sameprocedure as Example 30, except that morpholine was used instead of4-methylpiperazine.

¹H NMR (CD₃OD, ppm): δ 2.48 (2H, m), 2.64 (4H, br s), 3.41 (2H, t),3.77(8H, m), 7.45 (2H, m), 7.71 (1H, s); API MS(m/e)=380 [M+1].

Example 32 Synthesis ofN-[5-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-(1-piperidinyl)acetamide(32)

The title compound was obtained in a yield of 33% according to the sameprocedure as Example 30, except that piperidine was used instead of4-methylpiperazine.

¹H NMR (CD₃OD+CDCl₃, ppm): δ 1.45 (2H, br s), 1.68 (4H, m), 2.52 (2H,m), 2.61 (4H, br s), 3.20 (2H, s), 3.41 (2H, t), 3.81 (2H, t), 7.45 (2H,m), 7.77(1H, s); ESI MS(m/e)=378 [M+1].

Example 33 Synthesis ofN-[5-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-[4-(4-pyridinyl)phenyl]acetamide(33)

150 mg (0.373 mmol) of the compound obtained in Preparation 1 wasdissolved in 10 ml of tetrahydrofuran, and then 100 mg (0.373 mmol) of4-pyridinylphenylacetyl chloride was added thereto. The mixture washeated under reflux for 2 hours. After the solvent was removed underreduced pressure, the residue was treated with ethyl acetate and waterto give 16 mg of the title compound as a solid in a yield of 10%.

¹H NMR (DMSO-d₆, ppm): δ 2.38 (2H, m), 3.45 (2H, t), 3.67 (2H, t), 3.81(2H, s), 7.35 (1H, d), 7.46 (2H, d), 7.56 (3H, m), 7.72 (2H, d), 7.80(2H, d), 8.63 (3H, d), 10.69 (1H, s); API MS(m/e)=448 [M+1].

Example 34 Synthesis ofN-[5-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-[4-(4-piperidinyl)phenyl]acetamide(34)

130 mg (0.337 mmol) of the compound obtained in Preparation 1 was addedto 10 ml of tetrahydrofuran, and then 109 mg (0.502 mmol) of4-nitrophenylacetyl chloride was added thereto. The mixture was heatedunder reflux for 2 hours. The solvent was removed under reducedpressure, and then the residue was purified by silica gel columnchromatography (eluent:hexane/ethylacetate=1:4(v/v)) to give 30 mg ofthe title compound in a yield of 20%.

¹H NMR (CDCl₃+CD₃OD, ppm): δ 1.55(2H, m), 1.69 (4H, m), 2.51 (2H, m),3.09 (4H, m), 3.38 (2H, t), 3.70 (2H, s), 3.78 (2H, t), 6.95 (2H, d),7.26 (2H, m), 7.63 (1H, s); API MS(m/e)=454 [M+1].

Example 35 Synthesis ofN-[5-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-[4-(4-morpholinyl)phenyl]acetamide(35)

35-1) Synthesis of Ethyl 2-[4-(4-Morpholinyl)phenyl]-2-oxoacetate

0.25 g (1.53 mmol) of 4-phenylmorpholine was dissolved in 20 ml ofdichloromethane, was added 0.19 ml(1.68 mmol) of diethyloxalyl chlorideat −10° C. 3.4 ml (3.37 mmol) of 1.0 M titanium chloride solution(indichloromethane) was added dropwise at −10° C., and then the mixture wasstirred for 4 hours while keeping the temperature at −10° C. The mixturewas poured into ice water, and then extracted with diethyl ether threetimes. The resulting product was concentrated under reduced pressure,and then purified by silica gel column chromatography(eluent:hexane/ethylacetate=2/1 (v/v)) to give 0.15 mg of the titlecompound in a yield of 38%.

¹H NMR (CDCl₃ ppm): δ 1.40 (3H, t), 3.37 (4H, t), 3.84 (4H, t), 4.41(2H, q), 6.85 (2H, d), 7.92 (2H, d);

35-2) Synthesis of Ethyl 2-[4-(4-Morpholinyl)phenyl]acetate

0.5 g (1.901 mmol) of the compound obtained in Example 35-1) was addedto a solvent mixture (dioxane/water=10 ml/0.5 ml), and then 1.007 g(9.505 mmol) of sodium hypophosphite hydrate and 0.05 g ofpalladium-adsorbed activated carbon(10%) were added thereto. The mixturewas heated under reflux for 5 hours, and then cooled to roomtemperature. Additional 1.007 g (9.505 mmol) of sodium hypophosphitehydrate and 0.05 g of palladium-adsorbed activated carbon(10%) wereadded to the mixture. The mixture was stirred for another 5 hours. Theresulting suspension was filtered through celite, and the solvent wasremoved under reduced pressure. The residue was purified by silica gelcolumn chromatography (eluent:hexane/ethylacetate=2:1(v/v)) to give 0.37g of the title compound in a yield of 78%.

¹H NMR (CDCl₃+CD₃OD, ppm): δ 1.25 (3H, t), 3.14 (4H, m), 3.52 (2H, s),3.85 (4H, m), 4.14 (2H, m), 6.88 (2H, d), 7.18 (2H, d);

35-3) Synthesis of 2-[4-(4-Morpholinyl)phenyl]acetyl Chloride

0.35 g (1.41 mmol) of the compound obtained in Example 35-2) wasdissolved in 12 ml of tetrahydrofuran, and then 0.18 g (4.23 mmol) oflithium hydroxide in 4 ml of water was added thereto. The mixture wasstirred for 12 hours. The solvent was removed under reduced pressure.The residue was dissolved in 15 ml of dichloromethane, and then 5 molarequivalents of thionyl chloride was added thereto. The mixture wasstirred at room temperature for 4 hours. The solvent was removed byevaporation under reduced pressure to give 0.44 g of the title compound.The compound was used for subsequent reactions without furtherpurification processes.

35-4) Synthesis ofN-[5-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-[4-(4-morpholinyl)phenyl]acetamide

0.2 g (0.518 mmol) of the compound obtained in Preparation 1 was addedin 40 ml of tetrahydrofuran, and then 0.316 g (1.2 mmol) of4-morpholinylphenylacetyl chloride was added thereto. The mixture washeated under reflux for 7 hours. Subsequently, the solvent was removedunder reduced pressure. The residue was purified by silica gel columnchromatography (eluent:dichloromethane/methanol=19:1 (v/v)) to give 10mg of the title compound in a yield of 4%.

¹H NMR (CDCl₃+CD₃OD, ppm): δ 2.47 (2H, m), 3.10 (4H, m), 3.34 (2H, t),3.67 (2H, s), 3.75 (2H, t), 3.81 (4H, 4H), 6.87 (2H, d), 7.25 (2H, d),7.31(1H, d), 7.39 (1H, d), 7.67 (1H, s); API MS(m/e)=456 [M+1].

Example 36 Synthesis ofN-[5-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-[4-(3-thienyl)phenyl]acetamide(36)

106 mg (0.28 mmol) of the compound obtained in Preparation 1 was addedto 10 ml of tetrahydrofuran, and then 97 mg (0.41 mmol) of4-(3-thienyl)phenylacetyl chloride was added thereto. The mixture washeated under reflux for 2 hours. After the resulting mixture was cooledto room temperature, 5 ml of aqueous 1N sodium hydroxide solutionthereto. The mixture was stirred for 2 hours. The resultant wasextracted with ethyl acetate, and then washed with water three times.The solvent was removed under reduced pressure, and the residue was thentreated with methanol to give 51 mg of the title compound in a yield of41%.

¹H NMR (DMSO-d₆, ppm): δ 2.37 (2H, m), 3.45 (2H, t), 3.66 (2H, t), 3.74(2H, s), 7.35 (1H, d) 7.43 (2H, d), 7.46 (1H, d), 7.54 (1H, d), 7.56(1H, d), 7.63 (1H, dd), 7.70 (2H, d), 7.85 (1H, s), 10.63 (1H, s); ESIMS(m/e)=453 [M+1].

Example 37 Synthesis ofN-[5-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-[4-(4-morpholinylsulfonyl)phenyl]acetamide(38)

81 mg (0.21 mmol) of the compound obtained in Preparation 1 was added to10 ml of tetrahydrofuran, and then 91 mg (0.32 mmol) of4-(4-morpholinylsulfonyl)phenylacetyl chloride was added thereto. Themixture was heated under reflux for 2 hours. After the resulting mixturewas cooled to room temperature, 5 ml of aqueous 1N sodium hydroxidesolution thereto. The mixture was stirred for 2 hours. The resultant wasextracted with ethyl acetate, and then washed with water three times.The solvent was removed under reduced pressure, and the residue was thentreated with diethyl ether to give 69 mg of the title compound in ayield of 63%.

¹H NMR (DMSO-d₆, ppm): δ 2,39 (2H, m), 2,87 (4H, br), 3.45 (2H, t), 3.62(4H, br), 3.68 (2H, t), 3.90 (2H, s), 7.35 (1H, d), 7.47 (1H, d), 7.56(1H, s), 7.67 (2H, d), 7.73 (2H, d), 10.73 (1H, s); ESI MS(m/e)=520[M+1].

Example 38 Synthesis ofN-[5-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-(4-methoxyphenyl)acetamide(37)

60 mg of the title compound was obtained in a yield of 58% according tothe same procedure as Example 2, except that 4-methoxyphenylacetylchloride was used instead of 3-chlorophenylacetyl chloride.

¹H NMR (DMSO-d₆OD, ppm): δ 2.39 (2H, m), 3.46 (2H, t), 3.68 (4H, m),3.74 (3H, s), 6.91 (2H, d), 7.31 (3H, m), 7.45 (1H, d), 7.55 (1H, s);API MS(m/e)=401 [M+1].

Example 39 Synthesis ofN-[5-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-[4-(2-furyl)phenyl]acetamide(39)

24 mg (0.06 mmol) of the compound obtained in Preparation 1 was added to10 ml of tetrahydrofuran, and then 21 mg (0.09 mmol) of4-(2-furyl)phenylacetyl chloride was added thereto. The mixture washeated under reflux for 2 hours. After the resulting mixture was cooledto room temperature, 5 ml of aqueous 1N sodium hydroxide solutionthereto. The mixture was stirred for 2 hours. The resultant wasextracted with ethyl acetate, and then washed with water three times.The solvent was removed under reduced pressure, and the residue was thentreated with dichloromethane to give 13 mg of the title compound in ayield of 48%.

¹H NMR (DMSO-d₆, ppm): δ 2,38 (2H, m), 3.45 (2H, t), 3.69 (2H, t), 3.75(2H, s), 6.58 (1H, s), 6.91 (1H, s), 7.35 (1H, d), 7.45 (3H, m), 7.55(1H, s), 7.68 (2H, d), 7.73 (1H, s), 10.63 (1H, s); ESI MS(m/e)=437[M+1].

Example 40 Synthesis ofN-[5-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-4-[(4-methyl-1-piperazinyl)sulfonyl]phenylacetamide(40)

69 mg (0.178 mmol) of the compound obtained in Preparation 1 was addedto 10 ml of tetrahydrofuran, and then 112 mg (0.355 mmol) of4-[(4-methyl-1-piperazinyl)sulfonyl]phenylacetyl chloride was addedthereto. The mixture was heated under reflux for 2 hours. After theresulting mixture was cooled to room temperature, 5 ml of aqueous 1Nsodium hydroxide solution thereto. The mixture was stirred for 2 hours.The resultant was extracted with ethyl acetate, and then washed withwater three times. The solvent was removed under reduced pressure, andthe residue was then purified by silica gel column chromatography(eluent:dichloromethane/methanol=9/1 (v/v)) to give 12 mg of the titlecompound in a yield of 13%.

¹H NMR (CDCl₃, ppm): δ 2.26 (3H, s), 2.48 (4H, br), 2.51 (2H, m), 3.08(4H, br), 3.39 (2H, t), 3.47 (2H, s), 3.79 (2H, t), 7.30 (1H, d), 7.43(1H, d), 7.80(2H, d), 7.90 (1H, s), 8.43 (2H, d), 8.72 (1H, s); ESIMS(m/e)=533 [M+1].

Example 41 Synthesis of2-(1H-Benzimidazol-1-yl)-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide(41)

41-1) Synthesis of Benzyl3[(2-Bromoacetyl)amino]-5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-1-carboxylate

0.5 g (1.404 mmol) of the compound obtained in Preparation 1 was addedto 25 ml of tetrahydrofuran, and then 0.147 ml (1.2 eq) of bromoacetylbromide was added thereto. The mixture was heated under reflux for onehour. After the solvent was removed by evaporation under reducedpressure, the residue was purified by silica gel column chromatography(eluent:ethylacetate/hexane=4/1(v/v)) to give 0.47 g of the titlecompound in a yield of 66%.

1H NMR (CDCl₃+CD₃OD, ppm): δ 2.53 (2H, m), 3.42 (2H, t), 3.82 (2H, t),4.04 (2H, s), 5.47 (2H, s), 7.34 (3H, m), 7.45 (2H, m), 7.57 (1H, dd),7.79 (1H, s), 8.00 (1H, s).

41-2) Synthesis of2-(1H-Benzimidazol-1-yl)-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide

20 mg (0.169 mmol) of benzimidazole was dissolved in 10 ml ofN,N-dimethylformamide, and then 20 mg (0.5 mmol) of sodium hydride wasadded thereto. After 5 minutes, 70 mg (0.38 mmol) of the compound inExample 41-1 was added thereto. The mixture was stirred for one hour.The solvent was removed under reduced pressure, and the residue was thentreated with ethyl acetate to give 20 mg of the title compound in ayield of 35%.

¹H NMR (DMSO-d₆OD, ppm): δ 2.36 (2H, m), 3.44 (2H, t), 5.29 (2H, s),7.25 (2H, m), 7.35 (1H, d), 7.48 (1H, d), 7.59 (2H, m), 7.70 (1H, d),8.28 (1H, s); ESI MS(m/e)=411 [M+1].

Example 42 Synthesis ofN-[5-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-(4-ethoxyphenyl)acetamide(42)

22 mg of the title compound was obtained in a yield of 41% according tothe same procedure as Example 2, except that 4-ethoxyphenylacetylchloride was used instead of 3-chlorophenylacetyl chloride.

¹H NMR (DMSO-d₆OD, ppm): δ 1.32 (3H, t), 2.40 (2H, m), 3.46 (2H, t),3.67 (4H, m), 4.01 (2H, m), 6.90 (2H, d), 7.30 (3H, m), 7.45 (1H, d),7.55 (1H, s), 10.53 (1H, s); API MS(m/e)=413 [M+1].

Example 43 Synthesis ofN-[5-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-[4-(4-morpholinylmethyl)phenyl]acetamide(43)

1 g (2.591 mmol) of the compound obtained in Preparation 1 was added to80ml of tetrahydrofuran, and then 0.8 g (1.2 eq) of4-(bromomethyl)phenylacetyl bromide was added thereto. The mixture washeated under reflux for 2 hours. The solvent was removed under reducedpressure, and the residue was then purified by silica gel columnchromatography (eluent:hexane/ethylacetate=1/4(v/v)) to give 0.9 g ofthe title compound in a yield of 58%.

0.1 g (0.168 mmol) of the compound thus obtained was dissolved in 15 mlof N,N-dimethylformamide, and then 0.03 ml (2.0 eq) of morpholine and 50mg (2.0 eq) of anhydrous potassium carbonate were added thereto. Themixture was stirreat at 60° C. for 2 hours. The solvent was removedunder reduced pressure, and the residue was then purified by silica gelcolumn chromatography (eluent:dichloromethane/methanol=19/1(v/v)) togive 55 mg of the title compound in a yield of 65%.

¹H NMR (DMSO-d₆OD, ppm): δ 2.34 (4H, br s), 2.39 (2H, m), 3.46 (4H, m),3.57 (4H, m), 3.73 (4H, m) 7.27 (2H, d), 7.34 (2H, m), 7.36 (3H, m),7.46(1H, d), 7.57 (1H, s); API MS(m/e)=456 [M+1].

Example 44 Synthesis ofN-[5-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-4-[(4-methyl-1-piperazinyl)methyl]phenylacetamide(44)

44 mg of the title compound was obtained in a yield of 54% according tothe same procedure as Example 43, except that 4-methylpiperazine wasused instead of morpholine.

¹H NMR (CDCl₃+CD₃OD, ppm): δ 1.99 (3H, s), 2.24 (8H, m), 3.04 (2H, m),3.11 (2H, t), 3.22 (2H, s), 3.51 (4H, m), 7.01 (2H, d), 7.11 (4H, m),7.40 (1H, s); ESI MS(m/e)=482 [M+1].

Example 45 Synthesis ofN-[5-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-(4-nitrophenyl)acetamide(45)

386 mg (1.0 mmol) of the compound obtained in Preparation 1 was added to10 ml of tetrahydrofuran, and 299 mg (1.5 mmol) of 4-nitrophenylacetylchloride was added thereto. The mixture was heated under reflux for 2hours. After the mixture was cooled to room temperature, 5 ml of aqueous1N sodium hydroxide solution was added thereto. The mixture was stirredfor 2 hours. The resultant was extracted with ethyl acetate, and thenthe extracted ethyl acetate solution was washed with water three times.After the solvent was removed under reduced pressure, the residue wastreated with methanol to give 151 mg of the title compound as a solid ina yield of 36%.

¹H NMR (DMSO-d₆, ppm): δ 2.39 (2H, m), 3.54 (2H, t), 3.68 (2H, t), 3.93(2H, s), 7.34 (1H, d), 7.47 (1H, d), 7.57 (1H, s), 7.67 (2H, d), 8.22(2H, d), 10.72 (1H, s); ESI MS(m/e)=416 [M+1].

Example 46 Synthesis ofN-[5-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-[4-(1H-imidazol-1-ylmethyl)phenyl]acetamide(46)

50 mg of the title compound was obtained in a yield of 66% according tothe same procedure as Example 43, except that imidazole was used insteadof morpholine.

¹H NMR (CDCD3+CD₃OD, ppm): δ 2.28 (2H, m), 3.05 (2H, s), 3.16 (2H, t),3.53 (4H, m), 6.70 (2H, d), 6.89 (2H, d), 7.12 (2H, m), 7.22 (2H, d)7.55 (1H, s), 7.79 (1H, d); ESI MS(m/e)=451 [M+1].

Example 47 Synthesis ofN-[5-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-(4-phenyl-1H-imidazol-1-yl)acetamide(47)

10 mg of the title compound was obtained in a yield of 17% according tothe same procedure as Example 41, except that 4-phenylimidazole was usedinstead of benzimidazole.

¹H NMR (CDCl₃+CD₃OD, ppm): δ 2.25 (2H, m), 3.13 (2H, t), 3.53 (2H, t),4.71 (2H, s), 7.00 (1H, m), 7.11 (2H, m), 7.19 (3H, m), 7.46 (4H, m);ESI MS(m/e)=437 [M+1].

Example 48 Synthesis ofN-[5-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-(4-phenyl-1-piperazinyl)acetamide(48)

20 mg of the title compound was obtained in a yield of 32% according tothe same procedure as Example 41, except that 4-phenylpiperazine wasused instead of benzimidazole.

¹H NMR (CDCl₃+CD₃OD+DMSO-d₆, ppm): δ 2.42 (2H, m), 2.74 (4H, m), 3.21(4H, m), 3.38 (2H, t), 3.72 (4H, m), 6.75 (1H, t), 6.90 (2H, d), 7.17(2H, m) 7.37 (2H, dd), 7.42 (1H, d), 7.67 (1H, s); ESI MS(m/e)=456[M+1].

Example 49 Synthesis of2-[3,4-Dihydro-2(1H)-isoquinolinyl]-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide(49)

57 mg of the title compound was obtained in a yield of 68% according tothe same procedure as Example 41, except that3,4-dihydro-2(1H)-isoquinoline was used instead of benzimidazole.

¹H NMR (CDCl₃+CD₃OD, ppm): δ 2.56 (2H, m), 3.03 (4H, m), 3.43 (4H, m),3.85 (4H, m), 7.08 (4H, m), 7.45 (2H, m), 7.83 (1H, s); ESI MS(m/e)=426[M+1].

Example 50 Synthesis ofN-[5-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-[4-(4-chlorophenyl)-1-piperazinyl]acetamide(50)

20 mg of the title compound was obtained in a yield of 41 % according tothe same procedure as Example 41, except that4-(4-chlorophenyl)piperazine was used instead of benzimidazole.

¹H NMR (CDCl₃+CD₃OD, ppm): δ 2.55 (2H, m), 2.86 (4H, m), 3.36 (6H, m),3.44 (2H, t), 3.87 (2H, t) 6.87 (3H, m), 7.19 (1H, t), 7.47 (2H, m),7.82 (1H, s); ESI MS(m/e)=490 [M+1].

Example 51 Synthesis ofN-[5-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-[4-(4-methoxyphenyl)-1-piperazinyl]acetamide(51)

25 mg of the title compound was obtained in a yield of 53% according tothe same procedure as Example 41, except that4-(4-methoxyphenyl)piperazine was used instead of benzimidazole.

¹H NMR (CDCl₃+CD₃OD, ppm): δ 2.56 (2H, m), 3.44 (10H, m), 3.83 (5H, m),4.16 (2H, s), 6.92 (4H, m), 7.46 (2H, m), 7.85 (1H, s); ESI MS(m/e)=485[M+1].

Example 52 Synthesis ofN-[5-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-[4-(2-ethoxyphenyl)-1-piperazinyl]acetamide(52)

15 mg of the title compound was obtained in a yield of 20% according tothe same procedure as Example 41, except that4-(2-ethoxyphenyl)piperazine was used instead of benzimidazole.

¹H NMR (CDCl₃+CD₃OD, ppm): δ 1.48 (3H, t), 2.56 (2H, m), 2.91 (4H, m),3.22 (4H, m), 3.34 (2H, m), 3.43 (2H, t), 3.85 (2H, t), 4.11 (2H, m),7.00 (4H, m), 7.45 (2H, m), 7.85 (1H, s); API MS(m/e)=499 [M+1].

Example 53 Synthesis of2-[4-(4-Acetylphenyl)-1-piperazinyl]-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide(53)

25 mg of the title compound was obtained in a yield of 51% according tothe same procedure as Example 41, except that4-(4-acetylphenyl)piperazine was used instead of benzimidazole.

¹H NMR (CDCl₃+CD₃OD, ppm): δ 2.55 (4H, m), 2.86 (2H, m), 3.43 (8H, m),3.84 (2H, t), 4.06 (3H, s), 6.93 (2H, m), 7.46 (2H, m), 7.86 (1H, s),7.90 (2H, m); API MS(m/e)=498 [M+1].

Example 54 Synthesis ofN-[5-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-(4-phenoxyphenyl)acetamide(54)

25 mg of the title compound was obtained in a yield of 30% according tothe same procedure as Example 2, except that (4-phenoxyphenyl)acetylchloride was used instead of 3-chlorophenylacetyl chloride.

¹H NMR (CDCl₃+CD₃OD, ppm): δ 2.44 (2H, m), 3.39 (2H, t), 3.72 (4H, m),7.02 (5H, m), 7.34 (6H, m), 7.68 (1H, s); ESI MS(m/e)=463 [M+1].

Example 55 Synthesis ofN-[5-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-1-phenylcyclopentanecarboxamide(55)

24 mg of the title compound was obtained in a yield of 31% according tothe same procedure as Example 2, except that1-phenylcyclopentanecarbonyl chloride was used instead of3-chlorophenylacetyl chloride.

¹H NMR (CDCl₃+CD₃OD, ppm): δ 1.74 (4H, m), 2.04 (2H, m), 2.49 (4H, m),3.38 (2H, t), 3.68 (2H, t), 7.20 (5H, m), 7.38 (2H, m), 7.48 (1H, s);ESI MS(m/e)=425 [M+1].

Example 56 Synthesis of2-Cyclopentyl-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-phenylacetamide(56)

30 mg of the title compound was obtained in a yield of 38% according tothe same procedure as Example 2, except that2-cyclopentyl-2-phenylacetyl chloride was used instead of3-chlorophenylacetyl chloride.

¹H NMR (CDCl₃+CD₃OD, ppm): δ 1.61 (6H, m), 2.11 (1H, m), 2.51 (2H, m),2.79 (1H, m), 3.45 (4H, m), 3.78 (2H, t), 7.32 (5H, m), 7.54 (2H, m),(1H, s); ESI MS(m/e)=439 [M+1].

Example 57 Synthesis ofN-[5-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-phenylbutanamide(57)

35 mg of the title compound was obtained in a yield of 48% according tothe same procedure as Example 2, except that 2-phenylbutanoyl chloridewas used instead of 3-chlorophenylacetyl chloride.

¹H NMR (CDCl₃+CD₃OD, ppm): δ 0.94 (3H, t), 1.84 (1H, m), 2.17 (1H, m),2.46 (2H, m), 3.34 (2H, t), 3.57 (1H, t), 3.72 (2H, t), 7.23 (5H, m),7.38(2H, m), 7.56 (1H, s); ESI MS(m/e)=399 [M+1].

Example 58 Synthesis of t-Butyl4-(2-[5-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]amino-2-oxoethyl)-1,3-thiazol-2-ylcarbamate(58)

58-1) Synthesis of t-Butyl4-2-[(5-Nitro-1H-indazol-3-yl)amino]-2-oxoethyl-1,3-thiazol-2-ylcarbamate

2.0 g (10.204 mmol) of amino-N-hydroxy-5-nitrobenzenecarboxyimidoamidewas dissolved in 120 ml of tetrahydrofuran, and then 0.82 g (60%, 2.0eq) of sodium hydride was added thereto. After stirring 5 minutes atroom temperature, was added 3.5 g (1.2 eq) of ethyl2-2-[(t-butyloxycarbonyl)amino]-1,3-thiazol-4-ylacetate and stirred forone hour. After addition of 20 ml of N,N-dimethylformamide, furtherstirred under slight heating for 4 hours. The solvent was removed underreduced pressure, and the residue was then treated with ethyl acetateand water. The resulting precipitate was filtered and washed with waterand diethyl ether to give 1.9 g of the title compound in a yield of 42%.

58-2) Synthesis of t-Butyl4-2-[(5-Amino-1H-indazol-3-yl)amino]-2-oxoethyl-1,3-thiazol-2-ylcarbamate

1.9 g (4.24 mmol) of the compound obtained in Preparation 58-1) wasdissolved in methanol, and palladium-adsorbed activated carbon(10%) wasadded thereto. The mixture was stirred under hydrogen atmosphere for 2hours. The resulting suspension was filtered through celite, and thenthe filtrate was concentrated and dried to give 1.7 g of the titlecompound in a yield of 96%.

58-3) Synthesis of t-Butyl4-2-[(5-[(3-Chloropropyl)sulfonyl]amino-1H-indazol-3-yl)amino]-2-oxoethyl-1,3-thiazol-2-ylcarbamate

1.7 g (4.07 mmol) of the compound obtained in Preparation 58-2) wasdissolved in 100 ml of dichloromethane, and 1.53 ml (5.0 eq) of pyridineand 0.49 ml (1.0 eq) of 3-chloropropanesulfonyl chloride were addedthereto. The mixture was stirred at room temperature for 2 hours. Afterthe solvent was removed under reduced pressure, the residue was treatedwith ethyl acetate and water to give 0.8 g of the title compound as asolid in a yield of 37%.

¹H NMR (CDCl₃+CD₃OD, ppm): δ 1.35 (9H, s), 2.07 (2H, m), 3.02 (2H, t),3.45 (2H, t), 3.69 (2H, s), 6.60 (1H, s), 7.20 (2H, m), 7.60 (1H, s);API MS(m/e)=529 [M+1].

58-4) Synthesis of t-Butyl4-(2-[5-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]amino-2-oxoethyl)-1,3-thiazol-2-ylcarbamate

0.7 g (1.33 mmol) of the compound obtained in Preparation 58-3) wasdissolved in 50 ml of N,N-dimethylformamide, and 0.16 g (3.0 eq) ofsodium hydride was added thereto. The mixture was stirred for 3 hours.The solvent was removed under reduced pressure, and then the residue waspurified by silica gel column chromatography (eluent:n-hexane/ethylacetate=1/4(v/v)) to give 0.1 g of the title compound in a yield of 15%.

¹H NMR (CD₃OD, ppm): δ 1.53 (9H, s), 2.49 (2H, m), 3.42 (2H, t), 3.80(4H, m), 6.90 (1H, s), 7.44 (2H, m), 7.67 (1H, s); API MS(m/e)=493[M+1].

Example 59 Synthesis ofN-[5-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-4-[2-(2-ethoxyethoxy)ethoxy]phenylacetamide(59)

59-1) Synthesis of 2-(2-Ethoxyethoxy)ethyl 4-Methylbenzenesulfonate

432 mg (3.22 mmol) of 2-(2-ethoxyethoxy)ethanol was dissolved in 40 mlof dichloromethane, and 0.6 ml (4.19 mmol) of triethylamine and 614 mg(3.22 mmol) of p-toluenesulfonyl chloride were added thereto. Themixture was stirred at room temperature for 15 hours. After the solventwas removed under reduced pressure, 40 ml of water was added thereto.The mixture was extracted with 30 ml of ethyl acetate. The solvent wasremoved under reduced pressure to give 760 mg (2.64 mmol) of the titlecompound in a yield of 82%.

¹H NMR (CDCl₃, ppm): δ 1.20 (3H, t), 2.35 (3H, s), 3.35 (2H, q), 3.52(2H, t), 3.57-3.60 (4H, m), 4.08 (2H, t), 7.33 (2H, d), 7.78 (2H, d);FAB MS(m/e)=289 [M+1].

59-2) Synthesis of 2-4-[2-(2-Ethoxyethoxy)ethoxy]phenylacetic Acid

281 mg (0.97 mmol) of the compound obtained in Example 59-1) and 162 mg(0.971 mmol) of 4-hydroxyphenylacetic acid methyl ester were dissolvedin 30 ml of N,N-dimethylformamide, and then 58 mg (1.44mmol) of sodiumhydride(60%) was added thereto. The mixture was stirred at roomtemperature for one hour. After the reaction was completed, 3 ml ofmethanol was added thereto. The solvent was removed under reducedpressure, and 40 ml of water was added thereto. The mixture wasextracted with 30 ml of ethyl acetate. The solvent was removed underreduced pressure, and the residue was then purified by silica gel columnchromatography to give 64 mg (0.239 mmol) of the title compound in ayield of 24%.

¹H NMR (CDCl₃, ppm): δ 1.21 (3H, t), 3.34 (2H, q), 3.51 (2H, t),3.57-3.61 (4H, m), 3.82 (2H, s), 4.06 (2H, t), 6.86 (2H, d), 7.17 (2H,d); FAB MS(m/e)=269 [M+1].

59-3) Synthesis ofN-[5-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-4-[2-(2-ethoxyethoxy)ethoxy]phenylacetamide

60 mg (0.224 mmol) of the compound obtained in Example 59-2 wasdissolved in 15 ml of dichloromethane, and then 0.005 ml ofN,N-dimethylfornamide and 0.05 ml (0.685 mmol) of thionyl chloride wereadded thereto. The mixture was stirred for one hour. The solvent and theunreacted thionyl chloride were removed under reduced pressure. Theresultant was dissolved in 15 ml of tetrahydrofuran, and 79 mg (0.203mmol) of the compound obtained in Preparation 1 was added thereto. Themixture was heated to reflux for 2 hours. After cooled to roomtemperature, 1 ml (2 mmol) of aqueous 2N sodium hydroxide solution wasadded and the mixture was stirred at room temperature for 10 hours.After the reaction was completed, the mixture was concentrated and 30 mlof water was added. The mixture was extracted with 20 ml of ethylacetate and then concentrated again. 37 mg (0.074 mmol, yield 36%) ofthe title compound was isolated by silica gel column chromatography.

¹H NMR (CDCl₃, ppm): δ 1.20 (3H, t), 2.51 (2H, t), 3.32 (2H, q), 3.52(2H, t), 3.62-3.87 (10H, m), 4.15 (2H, t), 6.90 (2H, d), 7.27 (2H, d),7.50 (1H, d), 7.76(1H, d), 7,82 (1H, s), 9.80 (1H, s); FAB MS(m/e)=503[M+1].

Example 60 Synthesis of2-(2-Amino-1,3-thiazol-4-yl)-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide(60)

0.1 g (0.203 mmol) of the compound obtained in Example 58 was dissolvedin 15 ml of dichloromethane, and then 6 ml of trifluoroacetic acid wasadded thereto. The mixture was stirred at room temperature for twohours. The solvent was removed under reduced pressure to give 40 mg ofthe title compound in a yield of 50%.

¹H NMR (CD₃OD, ppm): δ 2.50 (2H, m), 3.42 (2H, t), 3.70 (2H, s), 3.80(2H, t), 6.45 (1H, s), 7.46 (2H, m), 7.70 (1H, s); ESI MS(m/e)=393[M+1].

Example 61 Synthesis of2-[4-(4-Bromophenyl)-1H-imidazol-1-yl]-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide(61)

10 mg of the title compound was obtained in a yield of 10% according tothe same procedure as Example 41, except that 4-(4-bromophenyl)imidazolewas used instead of benzimidazole.

¹H NMR (CD₃OD, ppm): δ 2.47 (2H, m), 3.39 (2H, t), 3.77 (2H, t), 5.05(2H, s), 7.43 (2H, s), 7.46 (2H, d), 7.52 (1H, s), 7.60 (2H, d), 7.69(1H, s), 7.75 (1H, s); ESI MS(m/e)=515 [M+1].

Example 62 Synthesis ofN-[5-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-[4-(2-naphthyl)-1H-imidazol-1-yl]acetamide(62)

20 mg of the title compound was obtained in a yield of 21% according tothe same procedure as Example 41, except that 4-(2-naphthyl)imidazolewas used instead of benzimidazole.

¹H NMR (CDCl₃+CD₃OD, ppm): δ 2.42 (2H, m), 3.34 (2H, t), 3.72 (2H, t),4.96 (2H, s), 7.38 (4H, m), 7.51 (1H, m), 7.77 (6H, m), 8.16 (1H, s);ESI MS(m/e)=487 [M+1].

Example 63 Synthesis of2-(4-[1,1′-Biphenyl]-4-yl-1H-imidazol-1-yl)-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide(63)

15 mg of the title compound was obtained in a yield of 10% according tothe same procedure as Example 41, except that4-([1,1′-biphenyl]-4-yl)imidazole was used instead of benzimidazole.

¹H NMR (CDCl₃+CD₃OD, ppm): δ 2.48 (2H, m), 3.36 (2H, t), 3.76 (2H, t),4.95 (2H, s), 7.29 (1H, m), 7.39 (3H, m), 7.45 (1H, d), 7.59 (5H, m),7.70 (2H, d), 7.77 (2H, d); ESI MS(m/e)=513 [M+1].

Example 64 Synthesis ofN-[5-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-[2-(ethylamino)-1,3-thiazol-4-yl]acetamide(64)Example 65 Synthesis of2-[2-(Diethylamino)-1,3-thiazol-4-yl]-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide(65)

36 mg (0.092 mmol) of the compound obtained in Example 60 was dissolvedin 15 ml of N,N-dimethylformamide, and then 0.016 ml (3.0 eq) ofacetaldehyde and 40 mg of sodium triacetoxyborohydride 40 mg were addedthereto. The mixture was stirred for 12 hours. The solvent was removedunder reduced pressure, and then the residue was purified by silica gelcolumn chromatography (eluent:dichloromethane/methanol=19/1(v/v)) togive 2 mg of the compound of Example 64 in a yield of 5% and 3 mg of thecompound of Example 65 in a yield of 7%.

Example 64N-[5-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-[2-(ethylamino)-1,3-thiazol-4-yl]acetamide

¹H NMR (CDCl₃+CD₃OD, ppm): δ 1.25 (3H, t), 2.52 (2H, m), 3.29 (2H, m),3.40 (2H, t), 3.66 (2H, s), 3.81 (2H, t), 6.36 (1H, s), 7.42 (2H, m),7.73 (1H, s); API MS(m/e)=421 [M+1].

Example 652-[2-(Diethylamino)-1,3-thiazol-4-yl]-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide

¹H NMR (CDCl₃+CD₃OD, ppm): δ 1.24 (6H, m), 2.53 (2H, m), 3.30 (2H, m),3.40 (2H, t) 3.40 (2H, m), 3.81 (2H, t), 4.39 (2H, s), 6.38 (1H, d),7.43 (2H, m), 7.71 (1H, d); ESI MS(m/e)=449 [M+1].

Example 66 Synthesis ofN-[5-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-(4-2-[2-(2-methoxyethoxy)ethoxy]ethoxyphenyl)acetamide(66)

68 mg (0.128 mmol) of the title compound was obtained in a yield of 34%according to the same procedure as Example 59, except that2-[2-(2-methoxyethoxy)ethoxy]ethanol was used instead of2-(2-ethoxyethoxy)ethanol.

¹H NMR (DMSO-d₆, ppm): δ 2.51 (2H, t), 3.22 (3H, s), 3.32-3.81 (16H, m),4.15 (2H, t), 6.91 (2H, d), 7.29 (2H, d), 7.40 (1H, d), 7.44 (1H, d),7.53 (1H, s); 10.50 (1H, s), FAB MS(m/e)=533 [M+1].

Example 67 Synthesis ofN-[5-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-(4-ethoxy-3-nitrophenyl)acetamide(67)

67-1) Synthesis of 4-Ethoxy-3-nitrophenylacetic Acid

1.08 g (6.0 mmol) of 4-ethoxyphenylacetic acid was dissolved in 12 ml ofacetic anhydride, and then 1.45 g (6.0 mmol) of cupric nitrate was addedthereto. The mixture was stirred at 0° C. for one hour. The resultingmixture was extracted with ethyl acetate, and then washed with waterthree times. The solvent was removed under reduced pressure, and thenthe residue was purified by silica gel column chromatography(eluent:dichloromethane/methanol=95/5(v/v)) to give 1.30 mg of the titlecompound in a yield of 94%.

¹H NMR (CDCl₃, ppm): δ 1.44 (3H, t), 3.62 (2H, s), 4.16 (2H, q), 7.02(1H, d), 7.41 (1H, d) 7.73 (1H, s); ESI MS(m/e)=224 [M+1].

67-2) Synthesis of 4-Ethoxy-3-nitrophenylacetyl Chloride

153 mg (0.68 mmol) of the compound obtained in Example 67-1 wasdissolved in dichloromethane, and then 0.15 ml (2.04 mmol) of thionylchloride was added thereto. The mixture was stirred for 2 hours. Thesolvent was removed under reduced pressure to give the title compoundquantatively.

67-3) Synthesis ofN-[5-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-(4-ethoxy-3-nitrophenyl)acetamide

190 mg of the title compound was obtained in a yield of 79% according tothe same procedure as Example 2, except that the compound obtained inExample 67-2 was used instead of 3-chlorophenylacetyl chloride.

¹H NMR (DMSO-d6, ppm): δ 1.34 (3H, t), 2.39 (2H, m), 2.04 (2H, t), 3.46(2H, t), 3.68 (2H, t), 3.78 (2H, s), 4.21 (2H, q), 7.34 (1H, d), 7.35(1H, d), 7.47 (1H, d), 7.56 (1H, s), 7.63 (1H, d), 7.87 (1H, s), 10.65(1H, s); ESI MS(m/e)=460 [M+1].

Example 68 Synthesis ofN-[5-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-(2-methylphenyl)acetamide(68)

32 mg of the title compound was obtained in a yield of 64% according tothe same procedure as Example 2, except that (2-methylphenyl)acetylchloride was used instead of 3-chlorophenylacetyl chloride.

¹H NMR (DMSO-d₆, ppm): δ 2.23 (3H, s), 2.39 (2H, m), 3.46 (2H, t), 3.68(2H, t), 3.77 (2H, s), 7.17 (3H, m), 7.31 (2H, m), 7.34 (1H, d), 7.46(1H, d), 7.58 (1H, s); ESI MS(m/e)=385 [M+1].

Example 69 Synthesis ofN-[5-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-[3-(ethylamino)phenyl]acetamide(69)

30 mg (0.78 mmol) of the compound obtained in Example 21 was added to 5ml of N,N-dimethylformamide, and 10 mg (0.234 mmol) of acetaldehyde, 50mg (0.234 mmol) of sodium triacetoxyborohydride and 14 mg (0.234 mmol)of glacial acetic acid were added. The mixture was stirred for 15 hours.After the removal of the solvent under reduced pressure, ethyl acetateand water was added. After basified with aqueous 1N sodium hydroxidesolution, ethyl acetate layer was collected and it was washed with waterthree times. The solvent was removed under reduced pressure, and theresidue was then purified by silica gel column chromatography(eluent:ethyl acetate) to give 10 mg of the title compound in a yield of31%.

¹H NMR (CDCl₃, ppm): δ 1.18 (3H, t), 2.39 (2H, m), 3.04 (2H, q), 3.61(2H, t), 3.64 (2H, s), 6.47 (1H, d), 6.54 (1H, s), 6.63 (1H, d), 7.03(1H, d), 7.10 (1H, t), 7.25 (1H, s), 7.60 (1H, s), 8.58 (1H, s); ESIMS(m/e)=414 [M+1].

Example 70 Synthesis of2-[3-(Diethylamino)phenyl]-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide(70)

The compound extracted with ethyl acetate in Example 69 was purified bysilica gel column chromatography (eluent:ethylacetate) to give 3 mg ofthe title compound in a yield of 9%.

¹H NMR (CDCl₃, ppm): δ 1.15 (6H, t), 2.48 (2H, m), 3.35 (6H, m), 3.74(2H, s), 3.76 (2H, t), 6.62 (3H, m), 7.21 (2H, d), 7.42 (1H, d), 7.76(1H, s), 8.07 (1H, s); ESI MS(m/e)=442 [M+1].

Example 71 Synthesis of2-(3,5-Dimethoxyphenyl)-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide(71)

50 mg of the title compound was obtained in a yield of 89% according tothe same procedure as Example 2, except that 3,5-dimethoxyphenylacetylchloride was used instead of 3-chlorophenylacetyl chloride.

¹H NMR (DMSO-d₆, ppm): δ 2.40 (2H, m), 3.46 (2H, t), 3.64 (2H, s), 3.68(2H, t), 3.74 (6H, s), 5.75 (1H, s), 6.40 (1H, s), 6.57 (1H, s), 7.35(1H, d), 7.46 (1H, d), 7.55 (1H, s), 10.57 (1H, s); ESI MS(m/e)=431[M+1].

Example 72 Synthesis ofN-[5-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-[4-(ethylamino)phenyl]acetamide(72)

15 mg (0.039 mmol) of the compound obtained in Example 21 was dissolvedin 5 ml of N,N-dimethylformamide, and 5 mg (0.117 mmol) of acetaldehyde,25 mg (0.117 mmol) of sodium triacetoxyborohydride and 7 mg (0.117 mmol)of glacial acetic acid were. After stirring for 15 hours, solvent wasremoved under reduced pressure, and ethyl acetate and water was added tothe residue. After basified with aqueous 1N sodium hydroxide solution,ethyl acetate layer was collected and it was washed with water threetimes. The solvent was removed under reduced pressure, and the residuewas then purified by silica gel column chromatography(eluent:ethylacetate) to give 5 mg of the title compound in a yield of31%.

¹H NMR (DMSO-d₆, ppm): δ 1.14 (3H, t), 2.39 (2H, m), 3.01 (2H, m), 3.46(2H, t), 3.52 (2H, s), 3.67 (2H, t), 5.39 (1H, s), 6.52 (2H, d), 7.09(2H, d), 7.34 (1H, d), 7.45 (1H, d), 7.54 (1H, s), 10.44 (1H, s); ESIMS(m/e)=414 [M+1].

Example 73 Synthesis of2-[4-(Diethylamino)phenyl]-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide(73)

The compound extracted with ethyl acetate in Example 73 was purified bysilica gel column chromatography (eluent:ethylacetate) to give 1 mg ofthe title compound in a yield of 6%.

¹H NMR (CDCl₃+CD₃OD, ppm): δ 1.11 (6H, t), 2.58 (2H, m), 3.31 (4H, q),3.35(2H, t), 3.65(2H, s), 3.79(2H, t), 6.65(2H, d), 7.16(2H, d),7.32(1H, d), 7.44 (1H, s), 7.75(1H, s); ESI MS(m/e)=442 [M+1].

Example 74 Synthesis of2-(3-Chloro-4-ethoxyphenyl)-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide(74)

47 mg of the title compound was obtained in a yield of 81% according tothe same procedure as Example 2, except that3-chloro-4-ethoxyphenylacetyl chloride was used instead of3-chlorophenylacetyl chloride.

¹H NMR (DMSO-d₆, ppm): δ 1.35(3H, t), 2.40(2H, m), 3.46(2H, t), 3.67(2H,s), 3.68(2H, t), 4.10(2H, q), 7.11(1H, d), 7.35(1H, d), 7.43(1H, s),7.46(2H, d), 7.55(1H, s), 10.59(1H, s); ESI MS(m/e)=449 [M+1].

Example 75 Synthesis of2-[4-(2-Aminoethoxy)phenyl]-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide(75)

75-1) Synthesis of Benzyl 2-Hydroxyethylcarbamate

944 mg(15.46 mmol) of 2-aminoethanol was dissolved in 50 ml ofdichloromethane, and then 1.8 ml(12.88 mmol) of benzyl chloroformate and2.7 ml(19.32 mmol) of triethylamine were added thereto. After thereaction was completed, the mixture was concentrated and 50 ml of waterwas added to obtain a white solid. The obtained white solid was filteredand dried to give 1.94 g(9.93 mmol) of the title compound in a yield of77%.

¹H NMR (CDCl₃, ppm): δ 3.34(2H, t), 3.71(2H, t), 5.10(2H, s),7.35-7.39(5H, m); FAB MS(m/e)=196 [M+1].

75-2) Synthesis of methyl2-[4-(2-[(benzyloxy)carbonyl]aminoethoxy)phenyl]acetate

950 mg(4.87 mmol) of the compound obtained in Example 75-1 and 809mg(4.87 mmol) of 4-hydroxyphenylacetic acid methyl ester were dissolvedin 70 ml of tetrahydrofuran, and then 0.84 ml(5.35 mmol) ofdiethylazodicarboxylate and 1.4 g(5.35 mmol) of triphenylphosphine wereadded thereto. The mixture was stirred at room temperature for one hour.After the reaction was completed, the solvent was removed under reducedpressure. Addition of 40 ml of diethyl ether to the residue causedprecipitation. The mixture was stirred for 30 minutes and filtered. Thefiltrate was purified by silica gel column chromatography to give 1.28g(3.73 mmol) of the title compound in a yield of 77%.

¹H NMR (CDCl₃, ppm): δ 3.54(3H, s), 3.59(2H, t), 3.67(2H, s), 4.01(2H,t), 5.10(2H, s), 6.82(2H, d), 7.17(2H, d), 7.35-7.39(5H, m); FABMS(m/e)=344 [M+1].

75-3) Synthesis of2-[4-(2-[(Benzyloxy)carbonyl]aminoethoxy)phenyl]acetic Acid

1.27 g(3.70 mmol) of the compound obtained in Example 75-2 was dissolvedin a solution consisting of 30 ml of tetrahydrofuran, 10 ml of methanoland 10 ml of water, and then 233 mg(5.55 mmol) of lithium hydroxide wasadded thereto. The mixture was stirred at room temperature for 15 hours.After the reaction was completed, the mixture was concentrated and 70 mlof water was added thereto. The mixture was adjusted to pH of 3 withaqueous 1N hydrochloric acid solution to obtain a white solid. The solidthus obtained was filtered, washed with water and dried to give 730mg(2.22 mmol) of the title compound in a yield of 60%.

¹H NMR (CD₃OD, ppm): δ 3.60(2H, t), 3.71(2H, s), 4.05(2H, t), 5.10(2H,s), 6.82(2H, d), 7.17(2H, d), 7.35-7.39(5H, m); FAB MS(m/e)=330 [M+1].

75-4) Synthesis of Benzyl3-(2-[4-(2-[(benzyloxy)carbonyl]aminoethoxy)phenyl]acetylamino)-5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-1-carboxylate

127 mg(0.386 mmol) of the compound obtained in Example 75-3 wasdissolved in 20 ml of dichloromethane, and then 0.001 ml ofN,N-dimethylformamide and 0.05 ml(0.685mmol) of thionyl chloride wereadded thereto. The mixture was stirred at room temperature for one hour.After the reaction was completed, the mixture was concentrated anddissolved in 20 ml of tetrahydrofuran. 99 mg(0.257 mmol) of the compoundobtained in Preparation 1 was added thereto, and the produced mixturewas heated to reflux for 2 hours. After the reaction was completed, 30ml of water was added and the mixture was extracted with 20 ml of ethylacetate. After removal of the solvent, concentrated, the residue waspurified by silica gel column chromatography to give 170 mg(0.243 mmol)of the title compound in a yield of 95%.

¹H NMR (CDCl₃, ppm): δ 2.53(2H, t), 3.39(2H, t), 3.60(2H, t), 3.71(2H,s), 3.83(2H, t), 4.05(2H, t) 5.11(2H, s), 5.47(2H, s), 6.85(2H, d),7.20(2H m), 7.38-7.40(2H, m), 7.66(1H, d), 8.11(1H, s); FAB MS(m/e)=698[M+1].

75-5) Synthesis of2-[4-(2-Aminoethoxy)phenyl]-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide

82 mg(0.118 mmol) of the compound obtained in Example 75-4 was dissolvedin a solution of 20 ml methanol and 10 ml of dichloromethane, andcatalytic amount of palladium-adsorbed activated carbon(10%) was addedthereto. The mixture was stirred under hydrogen atmosphere for 2 hours.After the reaction was completed, the product was filtered throughcelite. The removal of solvent under reduced pressure gave 32 mg(0.075mmol) of the title compound in a yield of 63%.

¹H NMR (CD₃OD, ppm): δ 2.50(2H, t), 3.30(2H, t), 3.34(2H, t), 3.43(2H,t), 3.78(2H, s), 4.05(2H, t), 6.95(2H, d), 7.34(2H, d), 7.40-7.52(2H,m), 7.66(1H, d); FAB MS(m/e)=430 [M+1].

Example 76 Synthesis of2-[2-(Acetylamino)-1,3-thiazol4-yl]-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide(76)

After 40 mg(0.102 mmol) of the compound obtained in Example 60 wasdissolved in 5 ml of N,N-dimethylformamide, were added 0.01 ml(1.5 eq)of acetic acid, 33 mg(1.7 eq) of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloric acid salt and32 mg(2.3 eq) of hydroxybenzotriazole. The mixture was stirred for 12hours. The solvent was removed under reduced pressure, and then theresidue was purified by silica gel column chromatography(eluent:dichloromethane/methanol=93/7(v/v)) to give 5 mg of the titlecompound in a yield of 11%.

¹H NMR (CDCl₃+CD₃OD, ppm): δ 2.53(2H, m), 2.66(3H, s), 3.42(2H, t),3.67(2H, s), 3.83(2H, t), 6.35(1H, s), 7.52(1H, dd), 7.84(1H, s),8.32(1H, d); ESI MS(m/e)=435 [M+1].

Example 77 Synthesis of2-(2-14-(Benzyloxy)benzyllamino-1,3-thiazol-4-yl)-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide(77)

77-1) Synthesis of2-[2-([4-(Benzyloxy)phenyl]methylideneamino)-1,3-thiazol-4-yl]-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide

After 50 mg(0.128 mmol) of the compound obtained in Example 60 wasdissolved in 8 ml of N,N-dimethylformamide, were added 81 mg(3.0 eq) of4-benzyloxybenzaldehyde, 0.1 g(4 eq) of sodium triacetoxyborohydride and0.4 ml(5 eq) of acetic acid. The mixture was stirred for 12 hours. Thesolvent was removed under reduced pressure, and then the residue waspurified by silica gel column chromatography (eluentdichloromethane/methanol=93/7(v/v)) to give 20 mg of the title compoundin a yield of 26%.

¹H NMR (CDCl₃+CD₃OD, ppm): δ 2.16(2H, m), 3.03(2H, t), 3.49(2H, t),3.64(2H, s), 4.87(2H, s), 6.79(1H, d), 6.91(1H, s), 7.11(6H, m),7.40(1H, s), 7.64(1H, d), 8.59(1H, s); API MS(m/e)=587 [M+1].

77-2) Synthesis of2-(2-[4-(Benzyloxy)benzyl]amino-1,3-thiazol-4-yl)-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide

20 mg(0.034 mmol) of the compound obtained in Example 77-1 was dissolvedin 20 ml of methanol, and then 60 mg of sodium borohydride was addedthereto. After stirring 3.5 hours, the solvent was removed under reducedpressure. Filtration of the precipitate caused by removal of solventgave the title compound quantatively.

¹H NMR (CDCl₃+CD₃OD, ppm): δ 2.45(2H, m), 3.35(2H, t), 3.68(2H, s),3.75(2H, t), 4.08(2H, m), 4.40(2H, s), 4.94(2H, s), 6.38(1H, s),6.83(2H, d), 7.25(3H, m), 7.32(2H, m), 7.36(2H, m), 7.44(2H, m),7.66(1H, s); API MS(m/e)=589 [M+1].

Example 78 Synthesis ofN-[5-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-(3-ethoxyphenyl)acetamide(78)

40 mg of the title compound was obtained in a yield of 48% according tothe same procedure as Example 2, except that 3-ethoxyphenylacetylchloride was used instead of 3-chlorophenylacetyl chloride.

¹H NMR (DMSO-d₆, ppm): δ 1.32(3H, t), 2.40(2H, m), 3.46(2H, t), 3.68(4H,m), 4.03(2H, q), 6.81(1H, d), 6.94(1H, d), 6.95(1H, s), 7.24(1H, t),7.35(1H, d), 7.46(1H, d), 7.55(1H, s), 10.59(1H, s); ESI MS(m/e)=415[M+1].

Example 79 Synthesis ofN-[5-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-[4-ethoxy-3-(4-morpholinylsulfonyl)phenyl]acetamide(79)

79-1) Synthesis of ethyl 2-[3-(chlorosulfonyl)-4-ethoxyphenyl]acetate

After addition of 208 mg(1.0 mmol) of ethyl 2-(4-ethoxyphenyl)acetate to0.2 ml(3.0 mmol) of chlorosulfuric acid dropwise at 0° C., the mixturewas warmed to room temperature and stirred for one hour, and then pouredinto ice water. After the resultant was extracted with ethyl acetate,the extracted ethyl acetate solution was washed with water three times.The solvent was removed under reduced pressure to give 110 mg of thetitle compound in a yield of 34%.

¹H NMR (CDCl₃, ppm): δ 1.26(3H, t), 1.53(3H, t), 3.60(2H, s), 4.16(2H,q), 4.27(2H, q), 7.05(1H, d), 7.58(1H, d), 7.84(1H, s).

79-2) Synthesis of Ethyl2-[4-Ethoxy-3-(4-morpholinylsulfonyl)phenyl]acetate

107 mg(0.35 mmol) of the compound obtained in Example 79-1 was dissolvedin dichloromethane, and then 61 mg(0.7 mmol) of morpholine and 71 mg(0.7mmol) of triethylamine were added thereto. The mixture was stirred forone hour. The solvent was removed under reduced pressure. After theresultant was extracted with ethyl acetate, the extracted ethyl acetatesolution was washed with water three times. The solvent was removedunder reduced pressure, and then the residue was purified by silica gelcolumn chromatography (eluent: hexane/ethyl acetate=1/1(v/v)) to give106 mg of the title compound in a yield of 85%.

¹H NMR (CDCl₃, ppm): δ 1.24(3H, t), 1.46(3H, t), 3.24(4H, t), 3.57(2H,s), 3.71(4H, t), 4.14(4H, q), 6.95(1H, d), 7.42(1H, d), 7.77(1H, s); ESIMS(m/e)=358 [M+1].

79-3) Synthesis of Ethyl2-[4-Ethoxy-3-(4-morpholinylsulfonyl)phenyl]acetic Acid

103 mg(0.288 mmol) of the compound obtained in Example 79-2 wasdissolved in a solution of 3 ml of tetrahydrofuran/1 ml of methano/1 mlof water, and then 35 mg(0.864 mmol) of lithium hydroxide was addedthereto. The mixture was stirred at room temperature for one hour. Afterthe solvent was removed under reduced pressure, aqueous 1N HCl solutionwas added thereto to adjust to pH of 3. After the resulting mixture wasextracted with ethyl acetate, the extracted ethyl acetate solution waswashed with water three times. The solvent was removed under reducedpressure to give 94 mg of the title compound in a yield of 99%.

¹H NMR (CDCl₃, ppm): δ 1.45(3H, t), 3.24(4H, t), 3.61(2H, s), 3.70(4H,t), 4.14(2H, q), 6.96(1H, d), 7.42(1H, d), 7.76(1H, s); ESI MS(m/e)=330[M+1].

79-4) Synthesis of Ethyl2-[4-Ethoxy-3-(4-morpholinylsulfonyl)phenyl]acetyl Chloride

94 mg(0.28 mmol) of the compound obtained in Example 79-3 was dissolvedin dichloromethane, and then 100 mg(0.84 mmol) of thionyl chloride wasadded thereto. The mixture was stirred at room temperature for 2 hours.The solvent was removed under reduced pressure to give the titlecompound quantatively.

79-5) Synthesis ofN-[5-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-[4-ethoxy-3-(4-morpholinylsulfonyl)phenyl]acetamide

80 mg of the title compound was obtained in a yield of 70% according tothe same procedure as Example 2, except that the compound obtained inExample 97-4 was used instead of 3-chlorophenylacetyl chloride.

¹H NMR (DMSO-d₆, ppm): δ 1.36(3H, t), 2.39(2H, m), 3.09(4H, t), 3.46(2H,t), 3.59(4H, t), 3.68(2H, t), 3.74(2H, s), 4.16(2H, q), 7.24(1H, d),7.35(1H, d), 7.46(1H, d), 7.54(1H, s), 7.62(1H, d), 7.79(1H, s),10.66(1H, s); ESI MS(m/e)=564 [M+1].

Example 80 Synthesis of2-[3-(Aminosulfonyl)4-ethoxyphenyl]-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide(80)

80-1) Synthesis of5-(2-[5-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]amino-2-oxoethyl)-2-ethoxybenzenesulfonylchloride

20 mg(0.048 mmol) of the compound obtained in Example 42 was added to0.2 ml of chlorosulfuric acid dropwise at 0° C. After stirring for 10minutes, the mixture was poured into ice water. The resultant wasextracted with ethyl acetate, and then the extracted ethyl acetatesolution was washed with water three times. The solvent was removed byevaporation under reduced pressure, and then the residue was purified bysilica gel column chromatography (eluent: ethyl acetate) to give 3 mg ofthe title compound in a yield of 12%.

¹H NMR (DMSO-d₆, ppm): δ 1.30(3H, t), 2.39(2H, m), 3.45(2H, t), 3.68(2H,t), 3.72(2H, s), 4.02(2H, q), 6.93(2H, d), 7.28(1H, d), 7.35(1H, d),7.45(1H, s), 7.76(1H, s), 10.61(1H, s);

80-2) Synthesis of2-[3-(Aminosulfonyl)-4-ethoxyphenyl]-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide

10 mg(0.019 mmol) of the compound obtained in Example 80-1 was dissolvedin 5 ml of acetonitrile, and then 0.1 ml of ammonia water was addedthereto. The mixture was stirred for 2 hours. The resultant wasextracted with ethyl acetate, and then the extracted ethyl acetatesolution was washed with water three times. After the solvent wasremoved by evaporation under reduced pressure, the residue was treatedwith diethyl ether to give 5 mg of the title compound as a solid in ayield of 56%.

¹H NMR (DMSO-d₆, ppm): δ 1.37(3H, t), 2.39(2H, m), 3.45(2H, t), 3.68(2H,t), 3.72(2H, s), 4.20(2H, q), 6.90(2H, s), 7.19(1H, d), 7.35(1H, d),7.46(1H, d), 7.54(1H, d), 7.55(1H, s), 7.80(1H, s), 10.67(1H, s); ESIMS(m/e)=494 [M+1].

Example 81 Synthesis ofN-[5-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-4-ethoxy-3-[(4-methyl-1-piperazinyl)sulfonyl]phenylacetamide(81)

7 mg(0.014 mmol) of the compound obtained in Example 80-1 was dissolvedin 5 ml of dichloromethane, and then 0.1 ml of N-methylpiperazine wasadded thereto. The mixture was stirred for 15 hours. The resultant wasextracted with ethyl acetate, and then the extracted ethyl acetatesolution was washed with water three times. After the solvent wasremoved by evaporation under reduced pressure, the residue was purifiedby silica gel column chromatography (eluent:dichloromethane/methanol=9:1) to give 2 mg of the title compound in ayield of 25%.

¹H NMR (CDCl₃, ppm): δ 1.42(3H, t), 2.28(3H, s), 2.44(4H, br), 2.49(2H,m), 3.28(4H, br), 3.39(2H, t), 3.72(2H, s), 3.74(2H, t), 4.05(2H, q),6.90(1H, d), 7.19(1H, d), 7.38(1H, d), 7.47(1H, d), 7.57(1H, s),7.89(1H, s), 8.66(1H, s); ESI MS(m/e)=577 [M+1].

Example 82 Synthesis of2-14-(2-Aminoethoxy)phenyl-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide(82)

82-1) Synthesis of Benzyl 2-hydroxyethylcarbamate

944 mg(15.46 mmol) of 2-aminoethanol was dissolved in 50 ml ofdichloromethane, and then 1.8 ml(12.88 mmol) of benzyl chloroformate and2.7 ml(19.32 mmol) of triethylamine were added thereto. The mixture wasstirred at room temperature for one hour. After the reaction wascompleted, the mixture was concentrated and 50 ml of water was addedthereto to obtain a white solid. The obtained white solid was filteredand dried to give 1.94 g(9.93 mmol) of the title compound in a yield of77%.

¹H NMR (CDCl₃, ppm): δ 3.34(2H, t), 3.71(2H, t), 5.10(2H, s),7.35-7.39(5H, m); FAB MS(m/e)=196 [M+1].

82-2) Synthesis of Methyl2-[4-(2-[(benzyloxy)carbonyl]aminoethoxy)phenyl]acetate

950 mg(4.87 mmol) of the compound obtained in Example 82-1 and 809mg(4.87 mmol) of 4-hydroxyphenylacetic acid methyl ester were dissolvedin 70 ml of tetrahydrofuran, and then 0.84 ml(5.35 mmol) ofdiethylazodicarboxylate and 1.4 g(5.35 mmol) of triphenylphosphine wereadded thereto. The mixture was stirred at room temperature for one hour.After the reaction was completed, the mixture was concentrated and 40 mlof diethyl ether was added thereto. The mixture was stirred for 30minutes and the obtained precipitate was filtered. The filtrate waspurified by silica gel column chromatography to give 1.28 g(3.73 mmol)of the title compound in a yield of 77%.

¹H NMR (CDCl₃, ppm): δ 3.54(3H, s), 3.59(2H, t), 3.67(2H, s), 4.01(2H,t), 5.10(2H, s), 6.82(2H, d), 7.17(2H, d), 7.35-7.39(5H, m); FABMS(m/e)=344 [M+1].

82-3) Synthesis of2-[4-(2-[(Benzyloxy)carbonyl]aminoethoxy)phenyl]acetic Acid

1.27 g(3.70 mmol) of the compound obtained in Example 82-2 was dissolvedin a solution consisting of 30 ml of tetrahydrofuran, 10 ml of methanoland 10 ml of water, and then 233 mg(5.55 mmol) of lithium hydroxide wasadded thereto. The mixture was stirred at room temperature for 15 hours.After the reaction was completed, the mixture was concentrated and 70 mlof water was added thereto. The mixture was adjusted to pH of 3 withaqueous 1N hydrochloric acid solution to obtain a white solid. The solidthus obtained was filtered, washed with water and dried to give 730mg(2.22 mmol) of the title compound in a yield of 60%.

¹H NMR (CD₃OD, ppm): δ 3.60(2H, t), 3.71(2H, s), 4.05(2H, t), 5.10(2H,s), 6.82(2H, d), 7.17(2H, d), 7.35-7.39(5H, m); FAB MS(m/e)=330 [M+1].

82-4) Synthesis of Benzyl3-(2-[4-(2-[(benzyloxy)carbonyl]aminoethoxy)phenyl]acetylamino)-5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-1-carboxylate

127 mg(0.386 mmol) of the compound obtained in Example 82-3 wasdissolved in 20 ml of dichloromethane, and then 0.001 ml ofN,N-dimethylformamide and 0.05 ml(0.685 mmol) of thionyl chloride wereadded thereto. The mixture was stirred at room temperature for one hour.After the reaction was completed, the mixture was concentrated and theresidue was dissolved in 20 ml of tetrahydrofuran. 99 mg(0.257 mmol) ofthe compound obtained in Preparation 1 was added thereto, and theproduced mixture was heated to reflux for 2 hours. After the solvent wasremoved under reduced pressure, 30 ml of water was added thereto andthen the mixture was extracted with ethyl acetate. After the solvent wasremoved under reduced pressure, the residue was purified by silica gelcolumn chromatography to give 170 mg(0.243 mmol) of the title compoundin a yield of 95%.

¹H NMR (CDCl₃, ppm): δ 2.53(2H, t), 3.39(2H, t), 3.60(2H, t), 3.71(2H,s), 3.83(2H, t), 4.05(2H, t), 5.11(2H, s), 5.47(2H, s), 6.85(2H, d),7.20(2H, d), 7.31-7.40(10H, m), 7.38-7.40(2H, m), 7.66(1H, d), 8.1 1(1H,s); FAB MS(m/e)=698 [M+1].

82-5) Synthesis of2-[4-(2-Aminoethoxy)phenyl]-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide

82 mg(0.118 mmol) of the compound obtained in Example 82-4 was dissolvedin a solution of 20 ml methanol and 10 ml of dichloromethan, andcatalytic amount of palladium-adsorbed activated carbon(10%) was addedthereto. The mixture was stirred under hydrogen atmosphere for 2 hours.After the reaction was completed, the mixture was filtered throughceltite. Removal of solvent under reduced pressure gave 32 mg(0.075mmol) of the title compound in a yield of 63%.

¹H NMR (CD₃OD, ppm): δ 2.50(2H, t), 3.30(2H, t), 3.34(2H, t), 3.43(2H,t), 3.78(2H, s), 4.05(2H, t), 6.95(2H, d), 7.34(2H, d), 7.40-7.52(2H,m), 7.66(1H, d); FAB MS(m/e)=430 [M+1].

EXPERIMENTAL EXAMPLE CDK2 and CDK4 Inhibitory Activity

Analytical experiments on inhibitory effects for CDK 2 and CDK 4proteins were performed in accordance with Kitagawa's method(Kitagawa,M. et al.; Oncogene, 9: 2549, 1994) and Carlson's method(Carlson, B. A.et al.; Cancer Research 56: 2473, 1996), respectively. CDK2 enzyme wasobtained from either extract from the worm cell co-infected withbaculovirus which expresses a CDK2 gene and baculovirus which expressesa cyclin A gene, or active enzyme purified therefrom. CDK4 was alsoobtained from either extract from the worm cell co-infected withbaculovirus which expresses a CDK4 gene and baculovirus which expressesa cyclin D1 gene. As substrates, histon H1 or Rb protein was used forCDK2, and Rb protein for CDK4. The radioactive activities in substrateswere determined by reacting compounds diluted with each concentrationwith a proper quantity of CDK2/cyclin A or CDK4/cyclin D1 and substrateprotein, and [gamma-32P labeled] ATP, and then separating thesubstrates.

Inhibitory abilities of inhibitors according to the present inventionfor each enzyme activity were expressed as IC50 values, which weredetermined in accordance with the method as described above. The resultsare shown in Table 1 below.

TABLE 1 Comp. CDK2 IC₅₀ CDK2 IC₅₀ No. (μM) (μM) 1 <0.05 <10 2 <0.05 <103 <0.1 <10 4 <0.05 <10 5 <0.5 >10 6 <0.05 <10 7 <0.05 <10 8 <0.05 <10 9<0.05 <10 10 <0.05 <10 11 <0.05 <10 12 <0.05 <10 13 <10 <100 14 <10 <10015 <0.05 <10 16 <0.05 <10 17 <0.05 <10 18 <0.05 <10 19 >100 >100 20<0.05 <10 21 <0.05 <10 22 <50 <50 23 <100 >100 24 <0.05 <10 25 <1 <10 26<0.05 <10 27 <0.05 <10 28 <0.05 <10 29 <0.05 <10 30 <10 <10 31 <10 <1032 <10 <10 33 <0.05 <10 34 <0.05 <10 35 <0.1 <10 36 <0.05 <10 37 <0.1<10 38 <0.1 <10 39 <0.05 <10 40 <1.0 <100 41 <0.05 <100 42 <0.05 <10 43<0.1 <10 44 <0.1 <10 45 <0.05 <10 46 <1.0 <100 47 <0.05 <10 48 <0.5 <1049 <1.0 <100 50 <10 <100 51 <10 <100 52 <10 <100 53 <10 <100 54 <0.1 <1055 <100 <1000 56 <100 <1000 57 <100 <1000 58 <0.1 <10 59 <0.1 <10 60<0.5 <100 61 <0.1 <10 62 <0.05 <10 63 <0.5 <100 64 <0.5 <100 65 <0.5<100 66 <0.1 <10 67 <0.05 <10 68 <0.1 <10 69 <0.5 <50 70 <0.5 <50 71<0.05 <10 72 <0.05 <10 73 <0.05 <10 74 <0.1 <50 75 <0.1 <50 76 <10 <10077 <10 <100 78 <0.05 <10 79 <1.0 <100 80 <1.0 <100 81 <1.0 <100 82 <1.0<100

What is claimed is:
 1. A compound represented by the following formula(1):

in which n represents 0, 1, 2 or 3, X represents oxygen, sulfur ornitrogen atom, R¹ and R² each independently represent hydrogen, amino,hydroxy, lower alkyl or cycloalkyl, or together form cycloalkyl, R³represents hydrogen; lower alkyl; phenyl or naphthyl which may beunsubstituted or substituted with one to three substituents selectedfrom the group consisting of hydroxy, halogen, nitro, amide, ester,carboxy, cyano, amidinyl, —O—R⁵, —NR⁶R⁷, phenyl, alkylsulfanyl, R⁸—SO₂—,lower alkyl, lower alkyl substituted with R⁹, pyridinyl, piperidinyl,morpholinyl, piperazinyl, thienyl and furyl; aromatic and bicyclicaromatic compounds bearing at least one heteroatom selected fromnitrogen, oxygen or sulfur atom; C₃₋₇-cycloalkyl bearing at least oneheteroatom selected from nitrogen, oxygen or sulfur atom; piperazinyl,imidazolyl, morpholinyl or piperidinyl which may be unsubstituted orsubstituted with one or two substituents selected from the groupconsisting of lower alkyl, phenyl, phenyl substituted with halogen,phenyl substituted with alkoxy, phenyl substituted with alkylcarbonyl,biphenyl and naphthyl; thiazole which may be unsubstituted orsubstituted with amino, mono- or di- lower alkylamino,alkylcarbonylamino, benzylamino, benzyloxycarbonylamino,benzyloxybenzylamino or alkoxycarbonylamino; benzodioxol; isoquinoline;indolyl; or benzimidazole wherein R⁵ represents phenyl, benzyl, loweralkyl, alkoxyalkyl, alkoxyalkoxylalkyl, alkoxyalkoxyalkoxyalkyl,aminoalkyl or mono- or di-alkylaminoalkyl, R⁶ and R⁷ are identifical ordifferent from each other and represent hydrogen, lower alkyl, oxygen orbenzyl, or joined to form a ring, and R⁸ and R⁹ represent eachindependently lower alkyl, amino, morpholinyl, piperazinyl,N-alkylpiperazinyl or imidazole, and R⁴ represents nothing when X isoxygen or sulfur atom, but represents hydroxy or alkoxy when X isnitrogen atom, pharmaceutically acceptable salt, solvated product orisomer thereof.
 2. The compound of formula (1), or pharmaceuticallyacceptable salt, solvated product or isomer thereof according to claim1, wherein n represents 1 or 2, X represents oxygen, sulfur or nitrogenatom, R¹ and R² each independently represent hydrogen, amino, hydroxy,lower alkyl or cycloalkyl, or together form cycloalkyl, R³ representshydrogen; lower alkyl; phenyl which may be unsubstituted or substitutedwith one to three substituents selected from the group consisting ofhydroxy, halogen, nitro, amide, cyano, amidinyl, —O—R⁵, —N R⁶ R⁷,phenyl, lower alkylsulfanyl, R⁸-SO₂—, lower alkyl, lower alkylsubstituted with R⁹, pyridiny, piperidinyl, morpholinyl, thienyl andfuryl; naphthyl; piperazinyl or imidazolyl which may be unsubstituted orsubstituted with one or two substituents selected from the groupconsisting of lower alkyl, phenyl, phenyl substituted with halogen,phenyl substituted with lower alkoxy, phenyl substituted with acetyl,biphenyl and naphthyl; morpholinyl; piperidinyl; thiazole which may beunsubstituted or substituted with amino, mono- or di- lower alkylamino,acetylamino, benzylamino, benzyloxyamino, benzyloxybenzylamino or loweralkoxycarbonylamino; benzodioxol; 3,4-dihydroisoquinoline; orbenzimidazole wherein R⁵ represents phenyl, benzyl, lower alkyl, loweralkoxyalkyl, polyethyleneglycolyl, aminoalkyl or mono- or di- loweralkylaminoalkyl, R⁶ and R⁷ are identifical or different from each otherand represent hydrogen, lower alkyl, oxygen or benzyl, or joined to forma ring, and R⁸ and R⁹ each independently represent lower alkyl, amino,morpholinyl, piperazinyl, N-alkylpiperazinyl or imidazole, and R⁴represents nothing when X is oxygen or sulfur atom, but representshydroxy or alkoxy when X is nitrogen atom.
 3. The compound of formula(1), or pharmaceutically acceptable salt, solvated product or isomerthereof according to claim 1, wherein the compound is selected from thegroup consisting of 1.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-phenylacetamide,2.2-(3-chlorophenyl)-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide,3.2-[4-(benzyloxy)phenyl]-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide,4.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-(4-hydroxyphenyl)acetamide,5.2-[4-(dibenzylamino)phenyl]-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide,6.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-[4-(methylamino)phenyl]acetamide,7.2-(4-aminophenyl)-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide,8.2-(4-chlorophenyl)-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide,9.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-(4-fluorophenyl)acetamide,10.2-[1,1′-biphenyl]-4-yl-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide,11.2-(3-bromophenyl)-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide,12.2-(4-bromophenyl)-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide,13.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-phenylethanethioamide,14.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-N′-hydroxy-2-phenylethaneimidoamide,15.2-(1,3-benzodioxol-5-yl)-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide,16.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-(1-naphthyl)acetamide,17.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-(2-naphthyl)acetamide,18.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-(3-nitrophenyl)acetamide,19. N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide,20.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-[4-(methylsulfanil)phenyl]acetamide,21.2-(3-aminophenyl)-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide,22.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]ethanethioamide,23.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-N′-hydroxyethaneimidoamide,24.2-(3,4-dichlorophenyl)-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide,25.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-3-phenylpropanamide,26.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-(4-isopropylphenyl)acetamide,27.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-(3-methylphenyl)acetamide,28.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-(4-methylphenyl)acetamide,29.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-[4-(methylsulfonyl)phenyl]acetamide,30.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-(4-methyl-1-piperazinyl)acetamide,31.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-(4-morpholinyl)acetamide,32.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-(1-piperidinyl)acetamide,33.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-[4-(4-pyridinyl)phenyl]acetamide,34.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-[4-(1-piperidinyl)phenyl]acetamide,35.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-[4-(1-morpholinyl)phenyl]acetamide,36.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-[4-(3-thienyl)phenyl]acetamide,37.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-[4-(4-morpholinylsulfonyl)phenyl]acetamide,38.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-(4-methoxyphenyl)acetamide,39.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-[4-(2-furyl)phenyl]acetamide,40.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-4-[(4-methyl-1-piperazinyl)sulfonyl]phenylacetamide,41.2-(1H-benzimidazol-1-yl)-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide,42.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-(4-ethoxyphenyl)acetamide,43.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-[4-(4-morpholinylmethyl)phenyl]acetamide,44.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-4-[(4-methyl-1piperazinyl)methyl]phenylacetamide,45.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-(4-nitrophenyl)acetamide,46.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-[4-(1H-imidazol-1-ylmethyl)phenyl]acetamide,47.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-(4-phenyl-1H-imidazol-1-yl)acetamide,48.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-(4-phenyl-1-piperazinyl)acetamide, 49.2-[3,4-dihydro-2(1H)-isoquinolinyl]-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide,50.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-[4-(4-chlorophenyl)-1-piperazinyl]acetamide,51.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-[4-(4-methoxyphenyl)-1-piperazinyl]acetamide,52.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-[4-(2-etboxyphenyl)-1-piperazinyl]acetamide,53.2-[4-(4-acetylphenyl)-1-piperazinyl]-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide,54.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-(4-phenoxyphenyl)acetamide,55.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-1-phenylcyclopentanecarboxamide,56.2-cyclopentyl-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-phenylacetamide,57.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-phenylbutanamide,58. t-butyl4-(2-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]amino-2-oxoethyl)-1,3-thiazol-2-ylcarbamate,59.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-2-4-[2-(2-ethoxyethoxy)ethoxy]phenylacetamide,60.2-(2-amino-1,3-thiazol-4-yl)-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide,61.2-[4-(4-bromophenyl)-1H-imidazol-1-yl]-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide,62.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-[4-(2-naphthyl)-1H-imidazol-1-yl]acetamide,63.2-(4-[1,1′-biphenyl]-4-yl-1H-imidazol-1-yl)-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide,64.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-[2-(ethylamimo)-1,3-thiazol-4-yl]acetamide,65.2-[2-(diethylamino)-1,3-thiazol-4-yl]-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide,66.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-(4-2-[2-methoxyethoxy)ethoxy]ethoxyphenyl)acetamide,67.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-(4-ethoxy-3-nitrophenyl)acetamide,68.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-(2-methylphenyl)acetamide,69.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-[3-(ethylamino)phenyl]acetamide,70.2-[3-(diethylamino)phenyl]-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide,71.2-(3,5-dimethoxyphenyl)-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide,72.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-[4-(ethylamino)phenyl]acetamide,73.2-[4-(diethylamino)phenyl]-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide,74.2-(3-chloro-4-ethoxyphenyl)-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide,75.2-[4-(2-aminoethoxy)phenyl]-N-[5(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol--3-yl]acetamide,76.2-[2-(acetylamino)-1,3-thiazol-4-yl]-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide,77.2-(2-[4-(benzyloxy)benzyl]amino-1,3-thiazol-4-yl)-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide,78.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-(3-ethoxyphenyl)acetamide,79.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-[4-ethoxy-3-(4-morpholinylsulfonyl)phenyl]acetamide,80.2-[3-(aminosulfonyl)-4-ethoxyphenyl]-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide,81.N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]-2-4-ethoxy-3-[(4-methyl-1-piperazinyl)sulfonyl]phenylacetamide,and 82.2-[4-(2-aminoethoxy)phenyl]-N-[5-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide.4. A composition of anti-cancer agent comprising the compound of formula(1), or pharmaceutically acceptable salt, solvated product or isomerthereof as defined in claim 1 as an active ingredient together with apharmaceutically acceptable carrier.
 5. A process for preparing thecompound of formula (1), or pharmaceutically acceptable salt, solvatedproduct or isomer thereof as defined in claim 1 which comprises a)reacting anthralilonitrile with hydroxylamine to produce an amidoxime ofthe following formula (2):

b) reacting the amidoxime with ester to produce a 3-aminoindazole of thefollowing formula (3):

wherein R¹, R², R³ and n are as defined in claim 1, c) protecting the1-position of 3-aminoindazole by t-butylcarbamate to produce a compoundof the following formula (4):

wherein R¹, R², R³ and n are as previously described, and Boc representst-butoxycarbonyl. d) reducing the nitro group at 5-C of formula (4) toproduce an amine of the following formula (5):

wherein, R¹, R², R³ and n are as previously described, and Bocrepresents t-butoxycarbonyl. e) reacting the amine of formula (5) withsulfonyl chloride to produce a sulfonamide of the following formula (6):

wherein, R¹, R², R³ and n are as previously described, and Bocrepresents t-butoxycarbonyl. e) cyclizing the compound of formula (6)through intramolecular ring-closing to synthesize a dioxoisothiazolidineof the following formula (7):

wherein R¹, R², R³ and n are as previously described, and Boc representst-butoxycarbonyl, and f) deprotecting the compound of formula (7). 6.The process for preparing the compound of formula (1), orpharmaceutically acceptable salt, solvated product or isomer thereofaccording to claim 5 which comprises a) reacting a compound of formula(1) wherein X is oxygen atom with Lawesson's reagent to produce acompound of formula (1) wherein X is sulfur atom; or b) reacting thecompound of formula (1) wherein X is sulfur atom with a compound of thefollowing formula (8): R⁴—NH₂  (8) wherein R⁴ is as defined in claim 1,to produce a compound of formula (1) wherein X is nitrogen atom.
 7. Aprocess for preparing the compound of formula (1), or pharmaceuticallyacceptable salt, solvated product or isomer thereof which compisesreacting an indazole intermediate of the following formula (9):

wherein Cbz represents benzyloxycarbonyl, with an acylhalide of thefollowing formula (10):

wherein R¹, R2, R³ and n are as defined in claim 1, and X′ representshalogen.
 8. A compound of formula (9):

wherein Cbz represents benzyloxycarbonyl, as an intermediate forpreparing the compound of formula (1), or pharmaceutically acceptablesalt, solvated product or isomer thereof as defined in claim 1.